BRPI0711892A2 - 2-alkoxy -3,4,5-trihydroxyalkyl amide-benzothiazepine, their preparation, their containing compositions and their use - Google Patents

Abstract

2- ALCOXY -3,4,5- TRI-HYDROXY-ALKYL AMIDA-BENZO TIAZEPINA, THEIR PREPARATION, THEIR COMPOSITIONS CONTAINING THEM, AND THEIR RESPECTIVE USE. The present invention relates notably to 2-alkoxy -3,4,5-trihydroxyalkylamide benzothiazepine, their preparation, their compositions containing them and their use as a medicament, in particular as anticancer agents.

Description

Patent Descriptive Report for "2-ALCOHY - 3,4,5-TRI-HYDROXY-ALKYL AMIDA-BENZO TIAZEPINE, THEIR PREPARATION, THEIR COMPOSITIONS CONTAINING THEM, AND THEIR USE".

The present invention relates in particular to 2-alkoxy -3,4,5-trihydroxyalkylamidobenzothiazepine, their preparation, the compositions containing them and their use as a medicament.

More particularly, and according to a first aspect, the invention relates to 2-alkoxy -3,4,5-trihydroxyalkylamidobenzothiazepine useful as anticancer agents.

2-Methoxy-3,4,5-trihydroxyalkylamides have been described in US 6,239,127, US 2001,0044433 A1, WO 01/85697, WO 00/29382, US 4831135, EP 687673, and Us 2002128474 A1. These documents essentially disclose analogues and derivatives of bengamide, a natural product isolated from a marine sponge, Jaspis coriacea.

These same products have been described in the literature: J. Org. Chem. (1996), 51 (23), 4494-7; J. Org. Chem. (2001), 66 (5), 1733-41; J. Med. Chem. 2001, 44, 3692-9.

The problem of solving the present invention is to obtain new products which exhibit anticancer activity. In addition to maintaining anticancer activity, certain of these new products may also have advantageous properties in relation to their pharmacological activity, such as their pharmacokinetics, bioavailability, solubility, stability, toxicity, absorption or metabolism.

The present invention relates to products corresponding to the following general formula (I):

<formula> formula see original document page 2 </formula>

wherein: a) R 1 is independently selected from the group consisting of (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 2 -C 12) alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (C 1 -C 6) alkyl C12) alkyl, C2 -C12 cycloalkyl alkenyl, C2 -C12 alkyl cyclin alkynyl, hetero (C1 -C12) cycloalkyl, hetero (C2 -C12) cycloalkenyl, hetero C2 -C12) alkynyl, aryl C 2 -C 12 alkyl, C 2 -C 12 aryl alkenyl, C 2 -C 12 aryl alkynyl, C 1 -C 12 heteroaryl alkyl, C 2 -C 12 hetero aryl alkenyl, C 2 -C 12 hetero aryl C12) alkynyl, the aryl group of each R1 being optionally substituted by one or more halogens;

b) R2 is selected from the group consisting of (C1-C6) alkyl, (C1-C6) aryl alkyl, hetero-aryl (C1-C6) alkyl, aryl, hetero aryl, (C1-C6) alkylthio (C1-C6) alkyl, di (C1-C6) lower alkyl (C1-C6) alkyl, aryloxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkyl;

c) R3 is selected from the group consisting of H, COO (R5), CONH (R5), CO (R5), O (R5), R5;

d) R4 is independently selected from the group consisting of H, F, Cl, Br, N (R5) 2, NO2, CN, COO (R5), CON (R5) 2, NHCO (R5), NHCOO (R5), OCONH (R5), O (R5), R5, or two substituents R4, attached to 2 adjoining phenyl carbons, together form a cycle selected from alkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R4 .

e) m is 0,1,2, 3, or 4;

f) X is chosen from S, SO or SO2;

g) R5 is independently chosen from double non-binder electrons, H, (C1-C12) alkyl, (C2-C12) alkenyl, (C2-C12) alkynyl, (C1-C12) alkyl halogen, (C1-C12) aryl alkyl, hetero (C 1 -C 12) aryl alkyl, hetero aryl (C 1 -C 12) aryl alkyl, aryl, hetero aryl, cycloalkyl, wherein each R 5 is optionally substituted by at least one substituent chosen from OH 1 halogen, (C 1 -C 4 alkyl, (C 1 -C 4) alkoxy, aryl (C 1 -C 4 alkyl), aryl, hetero aryl (C 1 -C 4) alkyl, hetero aryl, -N (CH 3) 2, -NH 2, CONH 2,

<formula> formula see original document page 3 </formula>

each of Rz is independently selected from the group consisting of H, COO (R5), CONH (R5), CON (R5) 2, CO (R5), R5, where each R5 is independently selected from (C1-C4 ) alkyl, (C1-C4) alkyl halo, (C1-C4) aryl alkyl, (C1-C4) alkyl heteroaryl, wherein each R5 is optionally substituted by a substituent chosen from OH1 halogen, (C1-C4) alkyl, (C1-C4) alkoxy, aryl (C1-C4) alkyl, aryl, heryl aryl (C1-C4) alkyl, heteroaryl;

provided that when R1 is (E) -CH = CH-C (CH3) 3. R 2 is methyl, X and S and m is O, so R 3 is not a hydrogen atom, a (3,5-difluorophenyl) methyl group or a -CH 2 -CH = CH 2 group.

The present invention relates to the products of formula (I) above, wherein R 1 is independently selected from the group consisting of (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 2 -C 12) alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, C 1 -C 12 aryl alkyl, C 2 -C 12 aryl alkenyl, C 2 -C 12 aryl alkynyl, hetero aryl (C 1 -C 12) alkyl, hetero aryl (C 2 -C 12) alkenyl, C2 -C12 heteroaryl aryl alkynyl.

The present invention relates to the products of formula (I) above, wherein R 2 is selected from the group consisting of (C 1 -C 6) alkyl, aryl (C 1 -C 6) alkyl, heteroaryl (C 1 -C 6) alkyl, aryl, hetero aryl, (C 2 -C 1 -C 6 C 12) alkenyl aryl, (C 2 -C 12) alkenyl hetero aryl, (C 1 -C 6) alkylthio, (C 1 -C 6) alkyl, di (C 1 -C 6) alkylamino, (C 1 -C 6) alkyl, C 1 -C 6 aryloxyalkyl.

According to the invention, R1 is preferably chosen from

from -C (R 6) = C (R 7) (R s), wherein R 6, R 7 and R 8 are independently selected from H, (C 1 -C 6) alkyl, cycloalkyl, hetero cyclyl, aryl, hetero aryl.

More preferably, R 1 is chosen from (E) -CH = CH-CH (CH 3) (C 2 H 5), (E) -CH = CH-CH (CH 3) 2, (E) -CH = CH-C (CH 3) , or between (E) -C (CH 3) = CH-CH (CH 3) (C 2 H 5), (E) -C (CH 3) = CH-CH (CH 3) 2, and (E) -C (CH 3) ) = CH-C (CH 3) 3.

More preferably, R1 is chosen from (E) -CH = CH-C5H9, (E) -CH = CH-C6H11, (E) -CH = CH- (CH2) 3 -CH3, (E) -CH = CH- C 6 H 5 in which phenyl is optionally substituted by a fluorine atom.

According to the invention, R2 is preferably methyl.

Among the objects of the present invention, a first group is characterized by the fact that X is S. A second group is characterized by the fact that X is SO and a third group is characterized by the fact that X is SO2.

Among the objects of the present invention, a fourth group is characterized by the fact that R3 is independently chosen from: methyl, a phenyl methyl group or a (3,5-difluoro-phenyl) methyl group. A fifth group is characterized by the fact that R3 is H.

Among the objects of the present invention, a sixth group is characterized by the fact that R4 is independently chosen from: F, Cl, Br, phenyl, cyano phenyl, trifluoro methyl, methoxy, phenoxy or 2 substituents R4, attached to 2 adjacent carbons of the phenyl together form a pyrazine cycle. A seventh group is characterized by the fact that m is 0.

Preferably, the invention relates to the products exemplified in table 1.

In another aspect, the invention relates to processes for preparing products of formula (I) or (Γ). Products of formula (Γ) are, if any, active precursors of products of formula (I). Products of formula (I) are obtained from products of formula (Γ) by processes described or by one or more reactions classic to the artisan, such as, for example, cyclopropanation, oxidation or separation. chiral. Notably, the products of examples 1 and 2 are obtained by oxidation of the product 6 of formula (Γ).

The products of formula (I) or (Γ) may be obtained by hydrolysis of a product of formula (II):

<formula> formula see original document page 5 </formula>

wherein R1, R2, R3, R4, X and m are as defined above.

The products of formula (II) may be obtained by reacting a product of formula (III): wherein R3, R4, X and m are as defined above. with a product of formula (IV):

<formula> formula see original document page 6 </formula>

wherein R1, R2 are as defined above.

The products of formula (I) or (I ') may also be obtained by reacting a product of formula (III) as defined above with a product of formula (V):

<formula> formula see original document page 6 </formula>

OH OH, wherein R1, R2 are as defined above.

The products of formula (V) may be obtained by hydrolysis of a product of formula (IV):

<formula> formula see original document page 6 </formula>

wherein R1, R2 are as defined above. Products of formula (V) for which R1 represents -CH = CH-R1 may further be obtained by hydrolysis of a product of formula (VII):

<formula> formula see original document page 6 </formula>

wherein R2 is as defined above to obtain a product of formula (VI):

<formula> formula see original document page 6 </formula>

OH 0H, wherein R2 is as defined above, which suffers from

a metathesis in order to obtain a product of formula (V): <formula> formula see original document page 7 </formula>

, for which R1 represents -CH = CH-R11 and RS represents a (C1-C6) alkyl, cycloalkyl, hetero cyclyl, aryl or heteroaryl group.

The products of formula (VII) may be obtained by double dehydration of a product of formula (VIII):

<formula> formula see original document page 7 </formula>

wherein R2 is as defined above.

Products of formula (Γ) and (II) as defined above except those for which R1 and (E) -CH = CH-C (CH3) 3, R2 is methyl, X is S, m is O, and R 3 is a hydrogen atom, a (3,5-difluoro-phenyl) methyl group or a -CH 2 -CH = CH 2 group are the object of the present invention.

Products of formula (III) for which X is S, R3 is H, methyl, phenyl methyl or (3,5-difluoro-phenyl) methyl and R4 is F, Cl, Br, phenyl, cyano phenyl, trifluoro methyl, methoxy or phenoxy, or m is O, except for those for which X is S, m is O, and R3 is a hydrogen atom or a (3,5-difluoro-phenyl) -methyl group having except for which X is S, R3 is phenyl methyl and R4 is trifluoro methyl or methoxy are an object of the present invention.

Products of formula (IV) and (V) for which R2 is methyl and R1 is - (E) -CH = CH-C5H9 or - (E) -CH = CH-C6H5 in which phenyl is substituted by a Fluorine atom are an object of the present invention.

Products of formula (VI) for which R2 is methyl are an object of the present invention. Products of formula (VII) for which R2 is methyl are an object of the present invention.

The products according to the present invention may exist in the base state, acid addition salts, solvates, hydrates or prodrugs.

Products according to the invention may be in non-chiral form, or racemic or enriched in a stereoisomer, or enriched in enantiomer; and may eventually be salified. Products for which the exocyclic amine-bound carbon is of (R) configuration are preferred.

A product according to the invention may be used for the manufacture of a medicament useful for preventing or treating a disease state, in particular a cancer.

The products of the present invention may also be used for the manufacture of medicaments useful for preventing or treating a condition in which neovascularization or angiogenesis is inappropriately performed, that is, in general cancers and in particular cancers such as Kaposi's sarcoma or infantile hemoangioma, but also, in rheumatoid arthritis, osteoarthritis and / or its associated pains, inflammatory bowel diseases such as hemorrhagic retocolitis or Crohn's disease, eye conditions such as Age-related macular degeneration, diabetic retinopathies, chronic inflammation, psoriasis.

Angiogenesis is a process of generating new capillaries from pre-existing vessels. Tumor angiogenesis (formation of new blood vessels), indispensable for tumor growth, is also one of the essential factors of metastatic dissemination (Oncogene. 2003 May 19; 22 (20): 3172-9; Nat Med. 1995 Jan; 1 (1 ): 27-31).

The present invention also relates to therapeutic compositions containing a compound according to the invention in association with a pharmaceutically acceptable excipient according to the mode of administration chosen. The composition may be in solid, liquid or liposome form.

Solid compositions include powders, capsules, tablets. Oral forms may also include solid forms protected from the acidic environment of the stomach. The supports used for solid forms consist notably of mineral supports such as phosphates, carbonates, or organic supports such as lactose, celluloses, starch or polymers. Liquid forms consist of support or dispersion solutions. They contain as dispersive support, either water, an organic solvent (ethanol, NMP or others) or mixtures of surfactants and solvents or complexing agents or solvents.

The liquid forms will preferably be injectable, and thus will have an acceptable formulation for such use.

Acceptable injection routes include intravenous, intraperitoneal, intramuscular, and subcutaneous routes, with the intravenous route being preferred.

The administered dose of the compounds of the invention will be adapted by the practitioner depending on the patient's route of administration and condition.

The compounds of the present invention may be administered alone or in admixture with other anticancer agents. Among the possible associations, we can mention:

* alkylating agents and notably cyclophosphamide, melmonan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocin, decarbazine, temarbolazine and procarbazine, hexamethylmelamine;

* platinum derivatives such as cisplatin, carboplatin or oxaliplatin

* antibiotic agents such as bleomycin, mithomycin, dectinomycin;

* antimicrotubule agents such as vinblastine, vincristine, vindezine, vinorelbine, taxoids (paclitaxel and docetaxel);

* anthracyclines, such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone;

* Group I and II topoisomerases such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex;

fluoropyrimidines, such as 5-fluorouracil, UFT, floxuridine;

cytidine analogs such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine;

adenosine analogs such as pentostatin, cytarabine or fludarabine phosphate;

* methotrexate and folinic acid;

* Enzymes and miscellaneous compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramine, dexrazoxane, amphostine, herceptin, as well as estrogen and androgenic hormones;

* anivascular agents, such as derivatives, such as combrestastatin or colchicine derivatives and their prodrugs;

* anivascular agents, such as combrastastatin derivatives, for example CA4P, chalcones or colchicine, for example ZD6126, and prodrugs thereof;

kinase inhibitors such as ertonilib or imatinib;

* biotherapeutic agents such as antibodies such as rituximab, bevacizumab, cetuximab, trastuzumab or alemtuzumab;

* proteasome inhibitors such as bortesomib.

Radiation treatment may also be associated with the compounds of the present invention. These treatments can be administered simultaneously, separately, sequentially. The treatment will be adapted by the practical, depending on the patient to be treated.

Definitions

The term "halogen" refers to an element chosen from F, Cl, Br, and I.

The term "alkyl" refers to a saturated straight or branched hydrocarbon substituent having from 1 to 12 carbon atoms. The substituents methyl, ethyl, propyl, 1-methyl ethyl, butyl, 1-methyl propyl, 2-methyl propyl, 1,1-dimethyl ethyl, pentyl, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-methyl pentyl, 2-methyl pentyl, 1-ethyl butyl, 2-ethyl butyl 3,3-dimethyl butyl, heptyl, 1-ethyl pentyl, octyl, nonyl, decyl, undecyl, and dodecyl are examples of alkyl substituents.

The term "alkenyl" refers to a straight or branched hydrocarbon substituent having one or more unsaturation having from 2 to 12 carbon atoms. The substituents ethylenyl, 1-methyl ethyl enyl, prop-1-enyl, prop-2-enyl, Ζ-1-methyl prop -1-enyl, E-1-methyl prop -1-enyl, Z-1,2- dimethyl-prop -1-enyl, E-1,2-dimethyl prop-1-enyl, but-1,3-dienyl, 1-methylidenyl-prop-2-enyl, Z-2-methyl but-1,3- dienyl, β-2-methyl but-1,3-dienyl, 2-methyl-1-methylidenyl prop-2-enyl, undec-1-enyl and undec-enyl are examples of alkylene substituent.

The term "alkynyl" refers to a straight or branched hydrocarbon substituent having at least two unsaturations carried by a pair of vicinal carbon atoms having from 2 to 12 carbon atoms. The ethinyl substituents; prop-1-ynyl; prop-2-ynyl; and but-1-ynyl are examples of the alkynyl substituent.

The term "aryl" refers to a mono- or polycyclic substituent having from 6 to 14 carbon atoms. The substituents phenyl, naphth-1-yl; naphth-2-yl; anthracen; 1,2,3,4-tetrahydro naphthyl-5-yl; and 1,2,3,4-tetrahydro naphthyl-6a are examples of aryl substituent.

The term "heteroaryl" refers to a mono- or polycyclic heteroaromatic substituent having from 1 to 13 carbon atoms and from 1 to 4 hetero atoms. Pyrrol-1-yl substituents; pyrrol2-yl; pyrrol3-yl; furila; thienyl; imidazolyl; oxazolyl; thiazolyl; isoxazolyl; isothiazolyl; 1,2,4-thia zolyl; oxadiazolyl; thiadiazolyl; tetrazolyl; pyridyl; pyrimidyl; pyrazinyl; 1,3,5-thiazinyl; indolyl; benzo [b] furyl; benzo [b] thienyl; indazolyl; benzimidazolyl; azaindole; quinoleyl; isoquinoleyl; carbazolyl; and acridyl are examples of substituent heteroaryl.

The term "hetero atom" here refers to an at least divalent atom other than carbon. N; THE; S; and If are examples of hetero atom.

The term "cycloalkyl" refers to a saturated or particularly unsaturated cyclic hydrocarbon substituent having from 3 to 12 carbon atoms. Cyclo propyl substituents; butyl cycle; pentyl cycle; pentenyl cycle; penta dienyl cycle; cyclohexyl; cyclohexenyl; cycloheptyl; bicyclo [2.2.1] heptyl; cyclooctyl; bicyclo [2.2.2] octyl; adamantyl; and perhydro naphthyl are examples of cycloalkyl substituent.

The term "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent having from 1 to 13 carbon atoms and from 1 to 4 hetero atoms. Preferably the saturated or partially unsaturated cyclic hydrocarbon substituent will be monocyclic and will contain 4 or 5 carbon atoms and 1 to 3 hetero atoms.

With reference to fused phenyl, when m is zero, it is understood to be unsubstituted phenyl (or substituted by 4 hydrogen atoms), and when m is 1, 2, 3, or 4, wherein 1, 2, 3 or 4 hydrogen atoms are replaced by a substituent R4.

The advantages of the invention will be more particularly illustrated by the following examples:

Abbreviations:

Ac Acetate; Bn is benzyl; 0 ° Celsius degree; cat. Catalyst; CCM thin layer chromatography; PCC preparative column chromatography; cm centimeter; δ chemical shift; d double; dd double of doubles; DMF dimethyl formamide; Deuterated DMSO-d 6 dimethyl sulfoxide; dt double of triples; eq. equivalent; ES +/- eletrospray (positive / negative modes); And ethyl; g gram; h time; Hz Hz; IC50 the inhibition constant at 50% activity; isopropyl iPr; j. day; J coupling constant; LCMS liquid chromatography coupled to a mass spectrometry; m multiple; Me methyl; mg milligram; MHz megahertz; mL millimeter; μΙ_ microliter; mm millimeter; μm micrometer; mmol millimol; min minute; N mol.L'1; Mp melting point; Phenyl; ppm parts per million; q fourfold; Rdt yield; Rf frontal relation; 1H NMR proton nuclear magnetic resonance; s singular; sl singular broad; t triple; RT room temperature; Butyl tertiary butyl; TFA trifluoroacetic acid; TTH tetrahydrofuran; tR retention times; U.V. ultraviolet; V volt

Ex1: N - [(1R, 3R) -5- (3,5-difluoro-benzyl) -1,4-dioxo-2,3,4,5-tetrahydro-1,5-benzo thiazepin 3-yl] - ((6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide and Ex2: N- [(1S-, 3R) -5- (3,5-difluorobenzyl) -1,4-dioxo -2,3,4,5-tetrahydro-1,5-benzo thiazepin-3-yl] - ((6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl -non-6-enamide Step 1: Preparation of (3R) - Tert-Butyl [5- (3,5-difluoro-benzyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] -carbamate (2)

<formula> formula see original document page 13 </formula>

In a 100 mL flask under stirring and argon atmosphere containing 40 mL of THF and 1.3 g of 1 (4.4 mmol), 177 mg of 60% suspension of sodium hydride are added at RT. oil (4.42 mmol). The medium is stirred for 1 hour, then 1.8 g (8.83 mmol) of 3,5-difluoro benzyl bromide is added.

The medium is left under stirring overnight. 100 ml of EtOAc are added, the organic phase is washed twice with 100 ml of water. The organic phase is dried over MgSO 4, filtered, then evaporated to dryness. 3 g of a yellow oil are obtained, which is chromatographed on a silica cartridge (120 g) and purified with a hepta / AcOEt mixture (gradient: 100% AcOEt 12) 1.59 g of product. 2.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.35 (s, 9H); 3.11 (t, J = 11.5 Hz, 1H); 3.48 (dd, J = 7.0 and 11.5 Hz, 1H); 4.15 (m, 1H); 5.03 (d, J = 16.0 Hz, 1H); 5.13 (d, J = 16.0 Hz, 1H); from 6.98 to 7.10 (m, 3H); 7.28 (broad t, J = 8.0 Hz 1H); 7.39 (broad d, J = 8.0 Hz, 1H); from 7.47 to 7.53 (m, 2H); 7.63 (broad d, J = 7.5 Hz, 1H).

Step 2: Preparation of (3R) -3-Amino-5- (3,5-difluoro-benzyl) -2,3-dihydro-5H-1,5-benzothiazepin-4-one hydrochloride (3)

<formula> formula see original document page 13 </formula>

1.59 g of 2 (3.78 mmol) are taken up in a 100 ml flask and 25 ml of a solution of hydrochloric acid in dioxane (4Μ) are added. Stir the medium for 5 hours at RT under argon. After evaporation of the solvent, 1.44 g of amine 3 is obtained as hydrochloride which is used directly for the next step.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.25 (t, J = 11.5 Hz, 1H); 3.75 (dd, J = 7.0 and 11.5 Hz, 1H); 3.94 (dd, J = 7.0 and 11.5 Hz, 1H); 5.09 (d, J = 16.0 Hz, 1H); 5.24 (d, J = 16.0 Hz, 1H); from 6.97 to 7.15 (m, 3H); 7.33 (m, 1H); from 7.48 to 7.59 (m, 2H); 7.68 (dd, J = 1.5 and 7.5 Hz, 1H); 8.63 (bs, 3H). Step 3: Preparation of (3R, 4R, 5S) -4-Hydroxy-5 - ((2E) - (2R) -1-Hydroxy-4,4-dimethyl-pent-2-enyl) -3-methoxy -dihydro-furan-2-one (5)

In a 250 ml flask containing 40 ml of water and 3.6 g of 4 which can be prepared according to the operating methods described in Org. Process Res. Dev. 2003, 7 (6), 856-865) in suspension are prepared. 17 ml of TFA in solution in 10 ml of water are added. Stir the medium for 1.5 hours at RT, then dilute the medium with 290 ml of water, freeze and lyophilize. 4 g of an oil which crystallizes in 20 ml of isopropyl ester at RT are obtained. After drying, washing with isopropyl ether, and vacuum drying at 40 ° C, 2.46 g of expected product 5 (white crystals) are obtained.

MP: 123 ° C

IC: m / z = 2621 MNH 4 *.

1H-NMR (400 MHz1 DMSOd6), δ (ppm): 1.00 (s, 9H); 3.41 (s, 3H); 3.93 (dd, J = 2.5 and 9.0 Hz, 1H); from 4.22 to 4.31 (m, 3H); 5.19 (d, J = 5.0 Hz, 1H); 5.42 (dd, J = 5.0 and 16.0 Hz, 1H); 5.43 (d, J = 4.5 Hz, 1H); 5.87 (d, J = 16.0 Hz, 1H).

IR (KBr): 3239; 2964; 2914; 1701; 1499; 1312; 1253; 1047 & 751 cm -1.

Step 4: Preparation of N - [(3R) -5- (3,5-difluoro-benzyl) -4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl ] - (6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide (6). <formula> formula see original document page 15 </formula>

Successively pour into 2.0 mL of THF in a Wheatton tube, under agitation and under argon atmosphere, 99 mg of 5 (405 μmol), 362 mg of 3 (1.0 mmol), 135 mg of 2-ethyl -sodium hexanoate (0.81 mmol). Stir at RT for 24 hours. 3 ml of ethyl acetate are added to the reaction medium. Wash successively with 3 ml HCl (1N) solution, then 5 ml saturated NaHCO3 solution and 3 ml water. The organic phase is dried over anhydrous magnesium sulfate, filtered, then evaporated to dryness. 300 mg of a brown solid are obtained, which is chromatographed on a silica cartridge (10 g, heptane / AcOEt purifier - gradient: 25% AcOEt). 123 mg of expected product is collected 6.

ES: 565 (+) = (M + H) (+); 547 (+) = (M + H) (+) --H 2 O 1H NMR (400 MHz1 DMSO-d6), δ (ppm): 0.95 (s, 9H); 3.20 (s, 3H); 3.21 (t, J = 12.0 Hz, 1H); from 3.32 to 3.47 (hidden, 1H); 3.48 (dd, J = 7.0 and 12.0 Hz, 1H); 3.50 (m partially hidden, 1H); 3.69 (d, J = 8.0 Hz, 1H); 3.92 (m, 1H); 4.30 (m broad, 2H); 4.45 (m, 1H); 4.54 (d, J = 4.5 Hz, 1H); 5.03 (d, J = 16.0 Hz, 1H); 5.21 (d, J = 16.0 Hz, 1H); 5.28 (dd, J = 7.0 and 16.0 Hz1 1H); 5.61 (broad d, J = 16.0 Hz, 1H); from 7.00 to 7.10 (m, 3H); 7.29 (m, 1H); from 7.45 to 7.55 (m, 2H); 7.61 (dd, J = 1.5 and 7.5 Hz, 1H); 8.49 (d, J = 8.0 Hz, 1H)

Step 4: Preparation of N - [(1R, 3R) -5- (3,5-difluoro-benzyl) -1,4-dioxo -2,3,4,5-tetrahydro-1,5-benzo thiazepin -3-yl] - ((6E) - (2R, 3R, 4S, 5R) - 3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide (Ex1) and N - [(1S, 3R) -5- (3,5-difluorobenzyl) -1,4-dioxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] - ((6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide (Ex2)

<formula> formula see original document page 15 </formula>

100 mg of 6 (177 μmol), 1 ml hexafluoro-2-propanol and 35 μl of 33% hydrogen peroxide are placed in a Wheatton tube under agitation and under argon atmosphere. Stirring is continued at RT for 5 hours. 70 μl of hydrogen peroxide are added, the medium is left for 24 hours. 3 ml of a Na 2 SO 4 solution are added to the reaction medium. Extract twice with 3 ml of CH 2 Cl 2. The organic phase is dried over anhydrous magnesium sulfate, filtered, then evaporated to dryness.

65 mg of crude product is obtained, which is chromatographed on a preparative silica plate (CH2 Cl2 / MeOH: 90/10 purifier). Expected dust 11.5 mg Ex1 and 28.5 mg expected Ex2 product are collected. ES: m / z = 579 (M-H) '

1 H NMR (400 MHz, DMSO-d 6), δ (ppm): 0.95 (s, 9H); 3.22 (s, 3H); from 3.26 to 3.32 (hidden, 1H); 3.38 (dd, J = 11.0 and 14.5 Hz, 1H); 3.52 (m, 1H); 3.71 (d, J = 8.0 Hz, 1H); 3.84 (dd, J = 7.5 and 14.5 Hz, 1H); 3.93 (m, 1H); 4.25 (d, J = 7.0 Hz, 1H); 4.32 (d, J = 5.5 Hz, 1H); 4.55 (d, J = 4.5 Hz, 1H); 4.67 (m, 1H); 4.75 (d, J = 16.5 Hz, 1H); 5.24 (d, J = 16.5 Hz, 1H); 5.29 (dd, J = 7.0 and 16.0 Hz, 1H); 5.61 (d, J = 16.0 Hz, 1H); 7.07 (tt, J = 2.0 and 9.5 Hz, 1H); 7.15 (m, 2H); 7.34 (d, J = 7.5 Hz, 1H); 7.42 (t, J = 7.5 Hz, 1H); from 7.63 to 7.68 (m, 2H); 8.59 (d, J = 7.5 Hz, 1H).

Ex 2: 1 H NMR (400 MHz, DMSO-d 6), δ (ppm): 0.95 (s, 9H); from 3.15 to 3.32 (hidden, 2H); 3.22 (s, 3H); 3.49 (m, 1H); 3.69 (d, J = 8.0 Hz 1H); 3.92 (m, 1H); 4.17 (t, J = 11.5 Hz, 1H); 4.30 (m, 2H); 4.44 (m, 1H); 4.55 (d, J = 4.5 Hz, 1H); 4.94 (d, J = 15.5 Hz, 1H); 5.19 (d, J = 15.5 Hz, 1H); 5.28 (dd, J = 7.0 and 16.0 Hz1 1H); 5.61 (d, J = 16.0 Hz, 1H); 6.96 (m, 2H); 7.13 (tt, J = 2.0 and 9.5 Hz, 1H); 7.53 (m, 1H); from 7.62 to 7.73 (m, 3H); 8.54 (d, J = 7.5 Hz, 1H).

Ex3: N - [(3R) -5-benzyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] - (6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl-non-6-enamide

<formula> formula see original document page 16 </formula> Step 1: Preparation of (3R) - [5-benzyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzo thiazepin - Tert-Butyl 3-yl] carbamate (7)

<formula> formula see original document page 17 </formula>

In a 50 ml flask, under stirring and argon atmosphere, containing 20 ml of THF and 315 mg of 1 (1.07 mmol), 42 mg of 60% suspended sodium hydride is added to the oil ( 1.07 mmol). The medium is stirred for 1 hour, and then 183 mg (1.07 mmol) of benzyl bromide is added. The medium is allowed to stir overnight, 30 ml of EtOAc are added and the organic phase is washed with 50 ml of water. The organic phase is dried over MgSO4, filtered, then evaporated to dryness. 0.4 g of a translucent oil is obtained, which is chromatographed on a silica cartridge (10 g) by purification with a CH 2 Cl 2 / MeOH mixture (gradient: 1 to 10% MeOH) 0.28 g of product 7. .

1H-NMR (300 MHz, DMSO-d6), δ (ppm): 1.35 (s, 9H); 3.09 (t, J = 11.5 Hz, 1H); 3.45 (dd, J = 7.0 and 11.5 Hz, 1H) 4.15 (m, 1H); 4.97 (d, J = 15.5 Hz, 1H); 5.20 (d, J = 15.5 Hz, 1H); from 7.13 to 7.30 (m, 6H); 7.39 (d, J = 8.0 Hz, 1H); 7.47 (m, 2H); 7.58 (d, J = 7.5 Hz, 1H).

Step 2: Preparation of (3R) -3-Amino -5-benzyl -2,3-dihydro-5H-1,5-benzothiazepin-4-one hydrochloride (8)

<formula> formula see original document page 17 </formula>

0.28 g of 7 (0.73 mmol) is taken up in a 50 ml flask and 6 ml of a solution of hydrochloric acid in dioxane (4M) is added. Stir the medium for 5 hours at RT under argon. After evaporation of the solvent and trituration with a mixture of CH 2 Cl 2 and isopropyl ether, after drying 0.24 g of amine 8 (yellow meringue) as hydrochloride is used directly in the next step.

1H-NMR (300 MHz, DMSO-Cl6), δ (ppm): 3.22 (t, J = 11.5 Hz, 1H); 3.73 (dd, J = 7.0 and 11.5 Hz, 1 Η); 3.91 (dd, J = 7.0 and 11.5 Hz, 1Η), 4.97 (d, J = 15.5 Hz, 1 1); 5.33 (d, J = 15.5 Hz, 1 Η); from 7.17 to 7.34 (m, 6H); from 7.48 to 7.59 (m, 2H); 7.62 (d, J = 7.5 Hz, 1H); 8.60 (bs, 3H).

1R (KBr): 2923; 2613; 1680; 1471; 1453; 1261; 1203; 774; 743; 698; 629 & 458 cm "1

Step 3: Preparation of N - [(3R) -5-Benzyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) - (R) - 2- [4R, 5S, 6R) -6- (1E) -3,3-dimethyl-but-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxinan-4-yl] - 2-methoxyacetamide (9)

<formula> formula see original document page 18 </formula>

50 mg of 4 (176 μmol), 113 mg of 8 (0.35 mmol), 73 mg of sodium 2-ethylhexanoate (50 mg of 4 (176 μmol), 73 mg of sodium 2-ethylhexanoate ( 0.44 mmol) in 1 mL of THF. Stirring is continued at RT for 24 hours. 3 ml of ethyl acetate are added to the reaction medium. Wash successively with 3 ml HCl (1N) solution, then 3 ml saturated NaHCO3 solution and 3 ml water. The organic phase is dried over anhydrous magnesium sulfate, filtered, then evaporated to dryness. The crude is chromatographed on a silica cartridge (12 g, CH2 Cl2 / MeOH-gradient scrubber: 10% MeOH 1), 100 mg of expected product collected 9.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 0.98 (s, 9H); 1.22 (s, 3H); 1.28 (s, 3H); 3.15 (t, J = 11.5 Hz, 1H); from 3.22 to 3.34 (hidden, 1H); 3.23 (s, 3H); 3.47 (m, 1H); 3.80 (d, J = 9.0 Hz, 1H); 3.90 (d, J = 9.0 Hz, 1H); 4.25 (d, J = 7.0 Hz, 1H); 4.36 (d, J = 8.0 Hz, 1H); 4.47 (m, 1H); 4.96 (d, J = 15.5 Hz, 1H); 5.24 (d, J = 15.5 Hz, 1H); 5.44 (dd, J = 7.0 and 16.0 Hz, 1H); 5.67 (d, J = 16.0 Hz, 1H); from 7.14 to 7.30 (m, 6H); 7.52 (m, 2H); 7.61 (d, J = 8.0 Hz, 1H); 8.52 (d, J = 8.5 Hz, 1H).

Step 4: Preparation of N - [(3R) -5-Benzyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] - (6E) - (2R , 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl-non-6-enamide (Ex3) <formula> formula see original document page 19 </formula>

In a 20 ml flask, 101 mg of 9 (178 μmol) in 0.85 ml of THF and 1.78 ml of 1N hydrochloric acid are mixed under stirring and under argon. Stirring is continued for 5 hours at RT. Then, the solution is cooled to 0 ° C. It is neutralized to pH 7.0 with 1N soda. Extract 2 times with 5 ml EtOAc. The organic phases are combined, dried over magnesium sulfate and filtered, then dried. 66 mg of crude product are obtained, which, after purification on a preparatory silica plate (CH2 Cl2 / MeOH: 90/10 purifier) gives 16.5 mg of expected product Ex3. IC: m / z = 546 MNhU +; M / Z = 529 MH +

1H-NMR (400 MHz, DMSOd6), δ (ppm): 0.95 (s, 9H); 3.17 (partially hidden t, J = 11.5 Hz, 1H); 3.21 (s, 3H); from 3.25 to 3.33 (hidden, 1H); from 3.40 to 3.53 (m, 2H); 3.69 (d, J = 8.0 Hz, 1H); 3.93 (m, 1H); 4.32 (m, 2H); 4.47 (m, 1H); 4.54 (broad d, J = 4.5 Hz, 1H); 4.94 (d, J = 15.5 Hz, 1H); from 5.25 to 5.32 (m, 2H); 5.61 (d, J = 16.0 Hz 1H); from 7.14 to 7.30 (m, 6H); from 7.45 to 7.54 (m, 2H); 7.59 (d, J = 7.5 Hz, 1H); 8.40 (d, J = 8.5 Hz 1H). Ex4: N - [(3R) -5-methyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] - (6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide

<formula> formula see original document page 19 </formula>

Step 1: Preparation of tert-Butyl (3R) - [5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiaze-pin-3-yl] carbamate ( 10)

<formula> formula see original document page 19 </formula>

In a 100 mL flask, under stirring and argon atmosphere, containing 15 mL of THF and 1.5 g of 1 (5.1 mmol), are placed at RT 224 mg of 60% sodium hydride suspended in the oil. (5.6 mmol). The medium is stirred for 1 hour, and then 0.80 g (5.6 mmol) of methyl iodide is added. The medium is allowed to stir for 1 hour and 30 minutes, 50 ml of CH 2 Cl 2 are added and the organic phase is washed twice with 30 ml of water and 1 time 30 ml of a saturated NaCl solution. The organic phase is dried over MgSO4, filtered, then evaporated to dryness. The crude is chromatographed on a silica cartridge (120 g) with a liver / EtOAc (75/25) mixture, yielding 1.31 g of product 10.

MP: 118 ° C +/- 2 ° C

ES: m / z = 309 MH +.

1H-NMR (400 MHz, DMSOd6), δ (ppm): 1.32 (s, 9H); 3.01 (t, J = 11.5 Hz, 1H); 3.29 (s, 3H); 3.41 (dd J = 7.0 and 11.5 Hz, 1H); 4.07 (m, 1H) 7.25 (d, J = 9.0 Hz, 1H); 7.30 (m, 2H); 7.57 (m, 2H); 7.63 (d, J = 7.5 Hz, 1H).

Step 2: Preparation of (3R) -Amino -5-methyl-2,3-dihydro-5H-1,5-benzothiazepin-4-one hydrochloride (11)

<formula> formula see original document page 20 </formula>

1.01 g of 10 (3.28 mmol) are taken up in a 100 ml flask and 20 ml of a solution of hydrochloric acid in dioxane (4M) are added. Stir the medium for 2 hours at RT under argon. After evaporation of the solvent, trituration with ether, and drying, 0.83 g of amine H (light yellow powder) as hydrochloride is obtained which is used directly in the next step.

IE: m / z = 208 M +.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.15 (t, J = 11.5 Hz, 1H); 3.35 (s, 3H); 3.67 (dd, J = 7.0 and 11.5 Hz1 1H); 3.85 (dd J = 7.0 and 11.5 Hz, 1H); 7.36 (m, 1H); 7.56 to 7.63 (m, 2H); 7.69 (m, 1H); 8.41 (bs, 3H).

Step 3: Preparation of N - [(3R) -5-Methyl-A-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] - (6E) - (2R (3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-hidden, J = 11.5 Hz, 1H); 3.21 (s, 3H); from 3.25 to 3.34 (hidden, 1H); 3.49 (m, 1H); 3.56 (dd, J = 7.0 and 11.5 Hz1 1H); 3.67 (d, J = 8.0 Hz, 1H); 3.91 (m, 1H); 4.29 (m broad, 2H); 4.41 (m, 1H); 4.53 (m broad, 1H); 5.28 (dd, J = 7.0 and 16.0 Hz, 1H); 5.62 (d, J = 16.0 Hz, 1H); 7.17 (d, J = 8.5 Hz, 1H); 7.52 (dd, J = 2.0 and 8.5 Hz, 1H); 7.67 (d, J = 2.0 Hz, 1H); 8.24 (broad d, J = 8.0 Hz, 1H); 10.2 (s, 1H).

Ex8: (6E) - (2R, 3R, 4S, 5R) -8-ethyl -3,4,5-trihydroxy-2-methoxy -N - ((3R) -5-methyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiaszepin-3-yl) -dec-6-enamide

<formula> formula see original document page 31 </formula>

Step 1: Preparation of (4R, 4aS, 7R, 7aR) -7-Methoxy-2,2-dimethyl-4-vinyl-tetrahydro [3,2-d] -1,3-dioxin-6-one one (28)

<formula> formula see original document page 31 </formula>

In a 4000 ml flask equipped with mechanical stirring, 178.2 g of PPh3 (0.679 mol), 84.1 g of imidazole (1.235 mol) and 2430 ml of anhydrous THF are charged under nitrogen. Caution: 156.8 g of bi-sublimated iodine (0.618 mol) is added cautiously, maintaining the temperature of the reaction mixture at 30 ° C. This medium is refluxed (66 ° C) for 1 hour, then 81 g of 27 (0.309 mol) are progressively added (which may be prepared according to the operating modes described in Org. Process Res. Dev. 2003, 7 ( 6), 856-865) at 66 ° C +/- 2 ° C. The homogeneous medium thus obtained is heated at reflux for 3 hours. Allow to return to 20 ° C +/- 5 ° C, then pour 1000 ml of a 10% NaHCO3 (effervescence, thermal) solution (pH 8.0-8.5). Then 185.5 g of NaaS2O3 is added until almost complete discoloration (appearance of a mineral precipitate). After stirring at 20 ° C +/- 5 ° C for 30 minutes, the solid is filtered and rinsed with THF. THF / H20 filtrate is partially concentrated - <formula> formula see original document page 22 </formula>

In a triple neck containing 0.91 g of L-Boc-Cys-OH (4.1 mmol), 7.2 ml of water and 1.0 g of NaHCO3 (2.89 mmol) is added dropwise. a solution of 12 (1.0 g, 4.1 mmol) in 8.6 mL of ethanol was dropped. The medium is refluxed for 2 hours and the ethanol concentrated. The aqueous phase is washed with 25 ml ether, once the ether phase is decanted, 25 ml EtOAc is added, and the aqueous phase is brought to pH 2-3 with HCl (1N). After stirring and decantation the aqueous phase is extracted again with 25 ml EtOAc. The organic phases are combined, dried over MgSO4, filtered, then evaporated to dryness. 2.0 g of expected product 13 (yellow oil) is obtained which is used directly for the next stage.

Step 2: Preparation of (2R) - (2-amino-6-chloro-A-trifluoro methyl-phenyl sulfanyl) -2-tert-butoxycarbonyl amino-propionic acid (14)

<formula> formula see original document page 22 </formula>

In an autoclave containing 1.85 g of 13 (4.2 mmol), 186 mg of Pd / C (10%) and 45 mL of MeOH was hydrogenated under 5 bars for 5.5 hours at 20 ° C. After Celite filtration of the catalyst and evaporation of the solvent, 1.45 g of expected product 14 is obtained which is used directly for the next stage.

1H-NMR (300 MHz, DMSO-d6), δ (ppm): 1.36 (bs, 9H); 3.01 (m, 1H); 3.10 (dd, J = 4.5 and 13.5 Hz, 1H); 3.98 (m, 1H); 6.25 (bs, 2H); 6.94 (d, J = 2.0 Hz, 1H); 7.00 (d, J = 2.0 Hz, 1H); 7.14 (broad d, J = 8.0 Hz, 1H); 12.8 (m high, 1H).

Step 3: Preparation of tert ((3R) -9-chloro-4-oxo-7-trifluoro methyl -2,3,4,5-tetrahydro-1,5-benzo thiazepin-3-yl) carbamate -butyl (15) <formula> formula see original document page 23 </formula>

In a 500 ml triple neck containing 1.35 g of 14 (3.3 mmol), 50 ml of CH 2 Cl 2 and 0.325 g of TEA (3.3 mmol) a solution of EDCI (0.624, 3.3 mmol, 1- (3-dimethyl amino propyl-3-ethylcarimide hydrochloride) and 1-hydroxy benzotriazole (0.44 g, 3.3 mmol) in 200 mL of CH 2 Cl 2. The reaction medium is allowed to return to RT, stirred for 24 hours, the medium is washed twice with water (200 ml), the organic phase is dried over MgSO4, filtered and evaporated to dryness. (70 g) with CH 2 Cl 2 / MeOH scrubber (gradient: 0 to 5% MeOH) 0.44 g of expected product 15 (meringue beige) is obtained.

1H-NMR (300 MHz, DMSO-d6), δ (ppm): 1.34 (s, 9H); 3.24 (t, J = 11.5 Hz, 1H); 3.58 (dd, J = 7.0 and 11.5 Hz, 1H); 4.12 (m, 1H); 7.34 (d, J = 8.0 Hz, 1H); 7.43 (bs, 1H); 7.84 (bs, 1H); 10.3 (s, 1H).

Step 4: Preparation of (3R) -3-Amino -9-chloro-7-trifluoro methyl-2,3-dihydro-5H-1,5-benzothiazepin-4-one hydrochloride (16)

<formula> formula see original document page 23 </formula>

In a 25 mL flask containing 582 mg of 15 (1.47 mmol), 11 mL of a solution of hydrochloric acid in dioxane (4M) is added. Stir for 4 hours at RT under argon. A white precipitate forms, is dried, washed with 3 ml dioxane, then 5 ml isopropyl ether. Thus 450 mg of amine 16 are obtained as hydrochloride.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.39 (t, J = 11.5 Hz 1H); 3.79 (dd, J = 7.0 and 11.5 Hz, 1H); 4.18 (dd, J = 7.0 and 11.5 Hz, 1H); 7.43 (d, J = 2.0 Hz, 1H); 7.91 (d, J = 2.0 Hz, 1H); 8.57 (bs, 3H); 10.9 (s, 1H). Step 5: Preparation of N - ((3R) -9-Chloro-A-oxo-7-trifluoro methyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) - ( 6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide (Ex5)

<formula> formula see original document page 24 </formula>

In a 25 ml flask under succession, 210 mg of 5 (0.43 mmol), 287 mg of 16 (0.86 mmol), 179 mg of 2-ethylacetate, under agitation and under argon atmosphere, sodium hexanoate (1.1 mmol) in 2.5 mL of THF. Stirring is continued at RT for 24 hours. 10 ml of ethyl acetate are added to the reaction medium. Successively wash 10 ml of HCl (1N) solution twice. The organic phase is dried over anhydrous magnesium sulfate, filtered, then evaporated to dryness. The crude is chromatographed over a silica cartridge (20 g, CH 2 Cl 2 / MeOH: 0 to 10% gradient MeOH purifier). 176 mg of expected product Ex5 is collected.

ES: m / z = 539 (M-H) "

1H-NMR (400 MHz, DMSOd6), δ (ppm): 0.95 (s, 9H); 3.19 (s, 3H); from 3.27 to 3.38 (hidden, 2H); 3.49 (m, 1H); 3.58 (dd, J = 7.0 and 11.5 Hz, 1H); 3.67 (d, J = 8.0 Hz, 1H); 3.93 (m, 1H); 4.27 (d, J = 7.5 Hz, 1H); 4.31 (d, J = 5.5 Hz, 1H); 4.45 (m, 1H); 4.55 (d, J = 4.5 Hz, 1H); 5.28 (dd, J = 7.0 and 16.0 Hz, 1H); 5.62 (d, J = 16.0 Hz, 1H); 7.42 (d, J = 2.0 Hz, 1H); 7.86 (d, J = 2.0 Hz, 1H); 8.35 (d, J = 7.5 Hz, 1H); 10.45 (s, 1H).

Ex6: N - ((3R) -9-bromo-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) - (6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl-non-6-enamide.

<formula> formula see original document page 24 </formula>

Step 1: Preparation of (3R) - (2-bromo-6-nitro-phenylsulfanyl) -2-tert-butoxycarbonylamino-propionic acid (18) <formula> formula see original document page 25 </formula>

In a triple neck containing 3.02 g of L-Boc-Cis-OH (13.6 mmol), 24 ml of water and 3.31 g of NaHCO3 (39.4 mmol), a solution of 17 (3.0 g, 13.6 mmol) in 28.5 ml of ethanol. Reflux the medium for 2 hours, then evaporate the ethanol. The aqueous phase is then washed with 50 ml ether, once the ether phase is decanted, 25 ml EtOAc are added and the aqueous phase is brought to pH2-3 with HCl (1N). After stirring and decantation, the aqueous phase is extracted again with 50 ml EtOAc. The organic phases are combined, dried over MgSO4, filtered and finally evaporated to dryness. 5.92 g of expected product 18 is obtained which is used directly for the next stage.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.36 (s, 9H); 3.12 (dd, J = 9.5 and 13.0 Hz, 1H); 3.32 (dd, J = 4.5 and 13.0 Hz, 1H); 3.93 (m, 1H); 7.09 (d, J = 8.5 Hz, 1H); 7.55 (t, J = 7.5 Hz, 1H); 7.90 (broad d, J = 7.5 Hz, 1H); 8.05 (broad d, J = 7.5 Hz, 1H); 12.7 (m broad, 1H).

Step 2: Preparation of (3R) -3- (2-amino-6-bromo-phenylsulfanyl) -2-tert-butoxycarbonylamino-propionic acid (19)

<formula> formula see original document page 25 </formula>

In an autoclave containing 5.92 g of 18 (14.1 mmol), 882 mg Pd / C (10%) and 100 mL MeOH, hydrogenate under 5 bars for 5 hours at 20 ° C. After filtration of the catalyst over Celite, the solvent is evaporated and 5.1 g of expected product 19 is obtained which is used directly for the next step.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.37 (s, 9H); 2.92 (dd, J = 9.5 and 13.0 Hz, 1H); 3.02 (dd, J = 4.5 and 13.0 Hz, 1H); 3.95 (m, 1H); 6.72 (broad d, J = 8.0 Hz, 1H); 6.83 (broad d, J = 8.0 Hz, 1H); 6.96 (t, J = 8.0 Hz, 1H); 7.22 (hidden m, 1H); 12.75 (m broad, 1H). Step 3: Preparation of tert-Butyl ((3R) -9-bromo-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) carbamate (20)

<formula> formula see original document page 26 </formula>

In a 500 ml neck containing 5.02 g of 19 (12.8 mmol), 150 ml of CH2 Cl2 and 1.30 g of TEA (12.8 mmol), an EDCI solution is introduced at 0 ° C. (2.46, 12.8 mmol, 1- (3-dimethylamino propyl) -3-ethylcarimimide hydrochloride) and 1-hydroxy benzothiazole (1.73 g, 12.8 mmol) in 65 mL of CH 2 Cl 2 . The reaction medium is allowed to return to RT and stirring is continued for 24 hours. The medium is washed twice with 500 ml of water. The organic phase is dried over MgSO4, filtered, then evaporated to dryness. The crude is chromatographed on a silica cartridge (300 g) with CH 2 Cl 2 / MeOH scrubber (gradient: 0 to 5% MeOH). 2.91 g of expected product 20 (beige meringue) is obtained.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.33 (s, 9H); 3.13 (t, J = 12.0 Hz, 1H); 3.52 (dd, J = 7.0 and 12.0 Hz, 1H); 4.04 (m, 1H); 7.17 (broad d, J = 8.0 Hz, 1H); 7.28 (d, J = 8.0 Hz, 1H); 7.34 (t, J = 8.0 Hz, 1H); 7.59 (broad d, J = 8.0 Hz, 1H); 10.15 (s, 1H).

Step 4: Preparation of (3R) -3-Amino-9-bromo -2,3-dihydro-5H-1,5-benzothiazepin-4-one hydrochloride (21)

<formula> formula see original document page 26 </formula>

In a 25 mL flask containing 500 mg of 20 (1.34 mmol), 10 mL of a solution of hydrochloric acid in dioxane (4M) is added. Stir for 4 hours at RT under argon. A white precipitate forms which is dried, washed with 3 mL of dioxane, then 5 mL of isopropyl ether. Thus 386 mg of amine 21 (beige solid) as hydrochloride is obtained. 1H-NMR (300 MHz, DMSO-Cl6), δ (ρρηι) :: 3.29 (t, J = 11.5 Hz1 1 Η); 3.78 (dd, J = 7.0 and 11.5 Hz, 1H); 3.96 (m, 1H); 7.19 (dd, J = 1.5 and 8.0 Hz, 1H); 7.38 (t, J = 8.0 Hz, 1H); 7.64 (dd, J = 1.5 and 8.0 Hz, 1H); 8.53 (bs, 3H); 10.75 (s, 1H).

Step 5: Preparation of N - ((3R) -9-Bromo-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) - (6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex6)

Under argon atmosphere 80 mg of 5 (327 pmol), 101 mg of 21 (327 pmol), 163 mg of sodium 2-ethylhexanoate (0.98 mmol) in 2.0 ml of THF. Stirring is continued at RT for 24 hours. 5 ml of ethyl acetate are added to the reaction medium. Wash successively with 5 ml of ethyl acetate in the reaction medium. Wash successively with 5 ml HCl (1 N) solution, 5 ml saturated NaHCO 3 solution and 5 ml water. The organic phase is dried over anhydrous magnesium sulfate, filtered, then evaporated to dryness. The crude is chromatographed over a silica cartridge (5 g, gradient CH 2 Cl 2 / MeOH: 10% MeOH purifier). 95 mg of expected product is collected Ex6 ES: m / z = 515 (M-H) '.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 0.96 (s, 9H); from 3.17 to 3.32 (partially hidden, 2H); 3.20 (s, 3H); 3.49 (m, 1H); 3.53 (partially hidden dd, J = 7.0 and 11.5 Hz, 1H); 3.68 (d, J = 8.0 Hz, 1H); 3.93 (m, 1H); 4.30 (m, 2H); 4.38 (m, 1H); 4.57 (d, J = 4.5 Hz, 1H); 5.29 (dd, J = 7.0 and 16.0 Hz, 1H); 5.62 (d, J = 16.0 Hz, 1H); 7.18 (broad d, J = 7.5 Hz, 1H); 7.35 (t, J = 7.5 Hz, 1H); 7.61 (broad d, J = 7.5 Hz, 1H); 8.29 (d, J = 7.5 Hz, 1H); 10.3 (s, 1H).

Ex7: N - ((3R) -8-chloro-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) - (6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-one

They are placed successively in a 25 ml flask under agenamide.

<formula> formula see original document page 28 </formula>

Step 1: Preparation of (3R) -3- (3-chloro-6-nitro-phenylsulfanyl) -2-tert-butoxycarbonylamino-propionic acid (23)

<formula> formula see original document page 28 </formula>

In a triple neck containing 1.26 g L-Boc-Cys-OH (5.70 mmol), 10 ml water and 1.38 g NaHCO3 (16.5 mmol), a solution is added dropwise. of 22 (1.0 g, 5.7 mmol) in 12 mL of ethanol. The medium is refluxed for 6 hours. Evaporate the ethanol. The aqueous phase is then washed with ether (30 mL), once the ether phase is decanted, the aqueous phase is acidified to pH2-3 with HCl (1N), then extracted with 30 mL of CH2 Cl2. The organic phases are combined, dried over MgSO4, filtered, then evaporated to dryness. 2.1 g of expected product 23 are obtained (yellow yellow which is used for the next stage. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.35 (s, 9H); 24 (dd, J = 10.0 and 13.5 Hz, 1H); 3.59 (dd, J = 4.0 and 13.5 Hz, 1H); 4.13 (m, 1H); 7.29 (broad d, J = 9.0 Hz, 1H); 7.48 (dd, J = 2.0 and 9.0 Hz, 1H); 7.72 (d, J = 2.0 Hz, 1H); 8.20 (d, J = 9.0 Hz, 1H); 13.0 (broad m, 1H).

Step 2: Preparation of (3R) -3- (2-amino-4-chloro-phenylsulfanyl) -2-tert-butoxycarbonylamino-propionic acid (24)

<formula> formula see original document page 28 </formula>

In a triple neck containing 2.1 g of 23 (5.55 mmol), 0.59 g of ammonium chloride and 70 ml of MeOH, 7.3 g of Zinc (0.11 mmol) is added. The reaction medium is stirred at RT for 2 hours and then heated to 75 ° C for 2 hours. Filter over celite, wash with 20 ml of boiling MeOH. Evaporate to dryness, the crude residue is taken up in 50 ml of water, then extracted with 2 times 50 ml of CH 2 Cl 2. The combined organic phases are dried over MgSO4, filtered and evaporated to dryness to give 1.62 g of expected product 24 (meringue cream) which is used for the next stage.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.36 (s, 9H); 2.93 (dd, J = 8.5 and 13.0 Hz, 1H); 3.12 (dd, J = 4.0 and 13.0 Hz, 1H); 3.93 (m, 1H); 5.49 (bs, 2H); 6.59 (broad d, J = 8.0 Hz, 1H); 6.70 (d, J = 8.5 Hz, 1H); 7.04 (dd, J = 2.5 and 8.5 Hz, 1H); 7.26 (d, J = 2.5 Hz, 1H).

Step 3: Preparation of tert-Butyl (3R) -8-chloro-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) carbamate (25)

<formula> formula see original document page 29 </formula>

In a 100 mL flask containing 1.62 g of 24 (4.67 mmol) and 30 mL of DMF1, 2.07 g of benzo triazol-1-yloxytris (dimethyl amino) phosphonium hexafluoride (4.67 mmol) is added. ) and 1.96 g of NaHCO3. The reaction medium is stirred for 24 hours at RT. 70 ml A-COEt are added, then washed with 50 ml HCl (1N), 50 ml saturated NaHCO 3 solution and 50 ml water. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The crude is chromatographed on a silica cartridge (40 g) with heptane / AcOEt scrubber (gradient AcOEt: 12 to 50%). 1.14 g of expected product 25 (pale yellow meringue) is obtained.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.33 (s, 9H); 3.10 (t, J = 11.5 Hz, 1H); 3.54 (dd, J = 7.0 and 11.5 Hz, 1H); 4.08 (m, 1H); 7.16 (d, J = 8.5 Hz 1H); 7.27 (d, J = 8.5 Hz, 1H); 7.51 (dd, J = 2.5 and 8.5 Hz, 1H); 7.64 (d, J = 2.5 Hz, 1H); 10.1 (s, 1H).

Step 4: Preparation of (3R) -3-Amino -8-chloro -2,3-dihydro-5H-1,5-benzothiazepin-4-one hydrochloride (26) <formula> formula see original document page 30 </formula>

In a 25 mL flask containing 500 mg of 25 (1.52 mmol), 10 mL of a solution of hydrochloric acid in dioxane (4M) is added. Stir for 4 hours at RT under argon. A white precipitate forms, which is dried, washed with 5 ml of dioxane, then 5 ml of isopropyl ether, after drying under vacuum, 510 mg of amine 26 (as hydrochloride) is obtained.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.26 (t, J = 11.5 Hz, 1H); 3.81 (dd, J = 7.0 and 11.5 Hz, 1H); 3.97 (dd, J = 7.0 and 11.5 Hz, 1H); 7.20 (d, J = 8.5 Hz, 1H); 7.55 (dd, J = 2.5 and 8.5 Hz, 1H); 7.70 (d, J = 2.5 Hz, 1H); 8.55 (bs, 3H); 10.65 (s, 1H).

Step 5: Preparation of N - ((3R) -8-Chloro-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) - (6E) - (2R , 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide (Ex7)

<formula> formula see original document page 30 </formula>

In a 25 ml flask under succession, under stirring and under an argon atmosphere of 5 (352 pmol), 187 mg of 26 (704 pmol), 146 mg of sodium 2-ethylhexanoate (0.88 mmol) in 2.0 mL of THF. Stirring is continued at RT for 24 hours. 5 ml of ethyl acetate is added to the reaction medium. Wash successively with 5 ml HCl (1 N) solution, 5 ml saturated aqueous NaHCO 3 and 5 ml water. The organic phase is dried over anhydrous magnesium sulfate, filtered, then evaporated to dryness. The crude is chromatographed over a silica cartridge (25 g, CH2 Cl2 / MeOH: 1: 10% gradient purifier). 70 mg of expected product Ex 7 is collected.

ES: m / z = 495 MNa +; m / z = 473 M H +.

1H-NMR (300 MHz, DMSO-d6) δ (ppm): 0.96 (s, 9H); 3.18 (t partially hidden, J = 11.5 Hz, 1H); 3.21 (s, 3H); from 3.25 to 3.34 (hidden, 1H); 3.49 (m, 1H); 3.56 (dd, J = 7.0 and 11.5 Hz1 1H); 3.67 (d, J = 8.0 Hz, 1H); 3.91 (m, 1H); 4.29 (m broad, 2H); 4.41 (m, 1H); 4.53 (m broad, 1H); 5.28 (dd, J = 7.0 and 16.0 Hz, 1H); 5.62 (d, J = 16.0 Hz, 1H); 7.17 (d, J = 8.5 Hz, 1H); 7.52 (dd, J = 2.0 and 8.5 Hz, 1H); 7.67 (d, J = 2.0 Hz, 1H); 8.24 (broad d, J = 8.0 Hz, 1H); 10.2 (s, 1H).

Ex8: (6E) - (2R, 3R, 4S, 5R) -8-ethyl -3,4,5-trihydroxy-2-methoxy -N - ((3R) -5-methyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiaszepin-3-yl) -dec-6-enamide

<formula> formula see original document page 31 </formula>

Step 1: Preparation of (4R, 4aS, 7R, 7aR) -7-Methoxy-2,2-dimethyl-4-vinyl-tetrahydro [3,2-d] -1,3-dioxin-6-one one (28)

<formula> formula see original document page 31 </formula>

In a 4000 ml flask equipped with mechanical stirring, 178.2 g of PPh3 (0.679 mol), 84.1 g of imidazole (1.235 mol) and 2430 ml of anhydrous THF are charged under nitrogen. Caution: 156.8 g of bi-sublimated iodine (0.618 mol) is added cautiously, maintaining the temperature of the reaction mixture at 30 ° C. This medium is refluxed (66 ° C) for 1 hour, then 81 g of 27 (0.309 mol) are progressively added (which may be prepared according to the operating modes described in Org. Process Res. Dev. 2003, 7 ( 6), 856-865) at 66 ° C +/- 2 ° C. The homogeneous medium thus obtained is heated at reflux for 3 hours. Allow to return to 20 ° C +/- 5 ° C, then pour 1000 ml of a 10% NaHCO3 (effervescence, thermal) solution (pH 8.0-8.5). Then 185.5 g of NaaS2O3 is added until almost complete discoloration (appearance of a mineral precipitate). After stirring at 20 ° C +/- 5 ° C for 30 minutes, the solid is filtered and rinsed with THF. The filtrate THF / H2 O is partially concentrated on the rotary evaporator at a temperature below 35 ° C. The aqueous concentrate is saturated with NaCl and extracted with 1500 ml of CH 2 Cl 2. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The residue is taken up in 2000 ml of an H2CVA ketone (75/25) mixture, the insolubles are filtered, and rinsed with the H2 O / Acetone (75/25) mixture. The filtrates are concentrated on the rotary evaporator at 50 ° C and 20 mbars, and filtered again over calcined glass (porosity # 4). The aqueous phase is saturated with NaCl, extracted 3 times with CH 2 Cl 2 (1000 mL, 500 mL and 250 mL). The organic phases are combined, dried over MgSO 4, filtered and evaporated to dryness to give 60 g of crude product, which is dissolved in 250 ml of CH 2 Cl 2. Then 30 g of silica are added to the solution. After stirring for 15 minutes, filter the silica, rinse 2 times with CH 2 Cl 2 (250 mL and 100 mL). The filtrate is concentrated to dryness and dried under 1 mbar at ° C to give 54.8 g of expected product 28 (white solid).

1H-NMR (300 MHz, DMSO-d6), δ (ppm): 5.85 (m, 1 H); 5.35 (d, 1H); 5.25 (d, 1H); 4.80 (m, 1H); 4.69 (m, 1H); 4.43 (d, 1H); 4.22 (m, 1H); 3.40 (s, 3 H); 1.49 (s, 3H); 1.30 (s, 3 H).

Step 2: Preparation of (3R, 4R, 5S) -4-Hydroxy-5 - ((1R) -hydroxy-allyl) -3-methoxy-dihydro-furan-2-one (29)

<formula> formula see original document page 32 </formula>

In a 100 ml flask containing 1.0 g of 28 (4.38 mmol), 10 mL of water and 14 mL of THF1 is added dropwise at 10 ° C 10 mL of TFA. The medium is allowed to return to RT and stirred for 1 night. The medium is then concentrated under reduced pressure at RT and 50 ml of water is added, frozen and lyophilized. The lyophilisate is slurried in heptane in the presence of a minimum of methanol, after evaporation of the solvents, 778 mg of expected 29 (white solid) is obtained. MS: m / z = 211 [M + Na] +, 189 [M + H] + 1 H NMR (400 MHz, DMSOd 6), δ (ρριτι): 3.42 (s, 3Η); 3.98 (dd, J = 2.5 and 9.0 Hz, 1Η); from 4.25 to 4.34 (m, 3H); 5.22 (dm, J = 10.5 Hz, 1H); 5.29 (d, J = 5.0 Hz, 1H); 5.44 (partially hidden d, J = 16.5 Hz, 1H); 5.46 (m, 1H); 5.97 (m, 1H).

Step 3: Preparation of ((3R, 4R, 5S) -5- ((2E) - (1R) -4-ethylhydroxyhex-2-enyl) -4-hydroxy-3-methoxyhydro - furan-2-one (30)

<formula> formula see original document page 33 </formula>

In a 5 mL vial, sac 100 mg of 29 (0.53 mmol), 0.52 g of 3-ethyl-1-pentene (5.3 mmol), 4 mL of CH 2 Cl 2 and 90 mg of Grubbs second catalyst generation (C46H65Cl2N2Pru, MW 848.98, 0.11 mmol). The red encapsulated brick solution is heated for 10 minutes at 60 ° C in the microwave (Smithsynthesizer, 300 Watt). The solvent is evaporated, the crude is chromatographed on a silica cartridge (25 g) and purified with a Heptane / AcOEt (55/4) mixture. 54 mg of expected product 30 (brown solid) is obtained.

1H-NMR (300 MHz, DMSO-d6), δ (ppm): 0.81 (t, J = 7.5 Hz, 6 H); 1.23 (m, 4H); from 1.32 to 1.49 (m, 2H); 1.78 (m, 1H); 3.42 (s, 3H) r 3.97 (d, J = 9.0 Hz, 1H); 4.20 to 4.31 (m, 3H); 5.11 to 5.75 (m, 4 H).

Step 4: Preparation of (6E) - (2R, 3R, 4S, 5R) -8-Ethyl-3,4,5-trihydroxy-2-methoxy -N - ((3R) -5-methyl-4-yl) oxo -2,3,4,5-tetrahydro -1,5-benzothiazepin-3-yl) dec-6-enamide (Ex 8)

<formula> formula see original document page 33 </formula>

In a 30 ml flask, successively, under stirring and under argon atmosphere, 50 mg of 30 (0.19 mmol), 71 mg of 11 (0.29 mmol), 64 mg of 2-ethylacetate and sodium hexanoate (0.39 mmol) in 2.0 mL of THF. Stirring is continued at RT for 96 hours. 4 ml CH 2 CF 3 are added to the reaction medium. Wash successively with 3 mL of a HCl (0.5N) solution, 3 mL of water. The aqueous phase is reextracted with 2 times 4 ml of CH 2 Cl 2. The combined organic phases are dried over anhydrous magnesium sulfate, filtered then evaporated to dryness. The crude is chromatographed over a silica cartridge (12g, scrubber, CH 2 Cl 2 / isopropanol: 95/5). 63 mg of expected product Ex8 is collected. ES: m / z = 465 (M-H) ".

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 0.75 to 0.82 (m, 6H); 1.10 to 1.37 (m, 4H); 1.70 (m, 1H); 3.06 (t, J = 11.5 Hz, 1H); 3.20 (s, 3H); 3.25 to 3.3 (m, 4H); 3.44 (dd, J = 7.0 and 11.5 Hz, 1H); 3.50 (m, 1H); 3.65 (d, J = 8.0 Hz, 1H); 3.92 (m, 1H); 4.30 (ml, 2H); 4.41 (m, 1H); 4.51 (m, 1H); 5.26 to 5.37 (m, 2H); 7.32 (m, 1H); 7.57 (m, 1H); 7.66 (d, J = 7.5 Hz, 1H); 8.20 (dl, J = 8.0 Hz, 1H).

Ex 9: (2R, 3R, $ s, 5R, 6E) -7-cyclopentyl -3,4,5-trihydroxy-2-methoxy -N - [(3R) -5-methyl-4-oxo-2 3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enamide

<formula> formula see original document page 34 </formula>

Step 1: Preparation of ((3R, 4R, 5S) -5 - [(1R, 2E) -3-Cyclopentyl-1-hydroxy-

In a 5 mL vial, introduce 100 mg (0.53 mmol) of 29.4 mL and CH2Cl2, 726 pL (5.3 mmol) of vinyl cyclopentane, then 90.2 mg (106 mmol) of Grubbs catalyst second generation. Heat the solution for 10 minutes at 60 ° C in the microwave. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified on a Biotage 12-M silica column (purifier: hept / AcOEt 40/60). Product 31 (76.3 mg, Rf = 0.35 under the purification conditions used) is obtained as a brown solid.

MS: m / z = 279 [M + Na] +, 257 [M + H] + 1 H NMR (300 MHz, DMSO-d 6), δ (ppm): 5.82 (dd, 1H, J = 8 Hz and 16 Hz ,), 5.50 (dd, 1H, J = 6Hz and 16Hz), 5.39 (d, 1H, J = 4.5Hz), 5.15 (d, 1H, J = 6Hz), 4.27 (m, 3H), 3.95 (dd, 1H, J = 3Hz and 8Hz), 3.41 (s, 3H), 2.43 (m, 1H), 1.73 (m, 2H), 1.56 (m, 4H), 1.26 (m, 2H).

Step 2: Preparation of (2R, 3R, 4S, 5R, 6E) -7-Cyclopentyl -3,4,5-trihydroxy-2-methoxy-N - [(3R) -5-methyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enaMIDA (Ex9)

<formula> formula see original document page 35 </formula>

In a 30 mL single neck, introduce 60 mg (234 pmol) of 31, 68.6 mg (281 pmol) of 11.3.3 mg (351 μιτιοΙ) of sodium 2-ethylhexanoate in 2.5 ml of THF. The solution is allowed to stir at room temperature for 1 week. The solution is then taken up in 5 mL CH 2 Cl 2, then washed with 4 mL 0.5 N HCl, then 4 mL water. The aqueous phase is then extracted with 2 x 5 mL of CH 2 Cl 2, then the organic phases are combined, dried over sodium sulfate, then filtered. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified over Biotage 12-M silica column (purifier: CH 2 Cl 2 / isopropanol 97/3). Ex9 (91.7 mg, Rf = 0.25 under the purification conditions used) is obtained as a white solid. MS: m / z = 929 [2M + H] +, 465 [M + H] +, 447 [(M-H 2 O) + H] +, 429 [(M-2 H 2 O) + H] + 1 H NMR (400 MHz1 DMSO-d 6): δ (ppm) = 8.24 (d, 1H, J = 8Hz), 7.67 (d, 1H, J = 8Hz), 7.57 (m, 2H), 7.33 (m, 1H), 5.57 (dd , 1H, J = 6.5 Hz and 15 Hz), 5.34 (dd, 1H, J = 6.5 Hz and 15 Hz), 4.53 (d, 1H, J = 4.5 Hz), 4.41 (m, 1H), 4.33 (d, 1H, J = 4.5 Hz), 4.30 (d, 1H, J = 5 Hz), 3.91 (m, 1H), 3.66 (d, 1H, J = 8 Hz), 3.47 (m, 1H), 3.41 (m, 1H), 3.3t (m, 1H), 3.29 (s, 3H), 3.20 (s, 3H), 3.07 (t, 1H, J = 12 Hz), 2.38 (m, 1 Η), 1.70 (m, 2Η ), 1.54 (m, 4Η), 1.22 (m, 2Η).

Χχ10: (3R, 4R, 5S) -4-hydroxy-5 - [(1R, 2Ε) -1-hydroxy-hept-2-en-1-yl] -3-methoxy dihydrofuran-2 (3H) - one (32)

<formula> formula see original document page 36 </formula>

Step 1: Preparation of (3R, 4R, 5S) -4-Hydroxy-5 - [(1R, 2E) -1-hydroxyhept-2-en-1-yl] -3-methoxydihydrofuran-2 (3H) -one ( 32)

<formula> formula see original document page 36 </formula>

In a 5 ml vial, introduce 100 mg (0.53 mmol) of 29, 4 mL of CH 2 Cl 2, 665 µl (5.3 mmol) of hexene-1, then 90.2 mg (106 pmol) of Grubbs catalyst. second generation. Heat the solution 10 min at 60 ° C in the microwave. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified over a Biota 12-S silica column (purifier: hept / AcOEt 40/60). Product 32 (57.3 mg, Rf = 0.29 under the purification conditions used) is obtained as a beige solid.

1H-NMR (300 MHz, DMSO-d6): δ (ppm) = 5.81 (m, 1H), 5.51 (dd, 1H, J = 5 Hz and 15.5 Hz), 5.38 (d, 1H, J = 4.2 Hz), 5.14 (d, 1H, J = 4.9 Hz), 4.26 (m, 3H), 3.96 (dd, 1H, J = 2.2 Hz and 8.8 Hz), 3.41 (s, 3H), 2.03 (q, 2H, J = 6 Hz), 1.32 (m, 4H), 0.87 (t, 3H, J = 8 Hz)

Step 2: Preparation of (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy-N - [(3R) -5-methyl-4-oxo -2,3, 4,5-tetrahydro-1,5-benzothiazepin-3-yl] undec-6-enamide (Ex 10)

<formula> formula see original document page 36 </formula>

In a 20 mL single neck, place 60 mg (246 μιτιοΙ) of 32, 72.1 mg (294 pmol) of 11, 61.2 mg (368 μηιοΙ) of sodium 2-ethylhexanoate in 2.5 ml of THF. The solution is allowed to stir at room temperature for 48 hours. The solution is then taken up with 5 mL CH 2 Cl, then washed with 4 mL 0.5 N HCl, then 3 mL water. The aqueous phase is then extracted with 2.5 mL of CH2 Cl2, then the organic phases are combined, dried over sodium sulfate, then filtered. The solvent is then evaporated to dryness under reduced pressure, then the residue on a 12-M biotage silica column (scrubber: CH 2 Cl 2 / isopropanol 98/2). Ex10 (30.2 mg, Rf = 0.19 under the purification conditions used) is obtained as a white solid.

MS: m / z (ES +) = 926 [2M + Na] +, 474 [M + Na] +, 453 [M + H] +, 435 [(M-H 2 O) + H] + 1 H NMR (400 MHz, DMSO-d 6): δ (ppm) = 8.24 (d, 1H, J = 8Hz), 7.66 (d, 1H, J = 8Hz), 7.56 (m, 2H), 7.33 (m, 1H), 5.55 (m , 1H), 5.36 (dd, 1H, J = 7.5Hz and 16Hz), 4.52 (d, 1H, J = 4Hz), 4.40 (m, 1H), 4.31 (d, 1H, J = 4.5Hz), 4.28 (d, 1H, J = 5Hz), 3.91 (m, 1H), 3.65 (d, 1H, J = 8Hz), 3.48 (m, 1H), 3.43 (m, 1H), 3.34 (m, 1H) ), 3.32 (s, 3H), 3.19 (s, 3H), 3.06 (t, 1H, J = 12 Hz), 1.95 (m, 2H), 1.26 (m, 4H), 0.86 (t, 3H, J = 7.5 Hz)

(2R, 3R, 4S, 5R, 6E) -7-cyclohexyl -3,4,5-trihydroxy-2-methoxy -N [(3R) -5-methyl-4-oxo-2 3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enamide

Step 1: Preparation of (3R, 4R, 5S) -5 - [(1R, 2E) -3-Cyclohexyl-1-hydroxy prop-2-en-1-yl] -4-hydroxy-3-methoxy dihydrofuran-2- (3H) -one (33)

<formula> formula see original document page 37 </formula>

In a 5 mL vial, introduce 100 mg (0.53 mmol) of 29.4 mL of CH 2 Cl 2, 728 pL (5.3 mmol) of vinyl cyclohexane, then 90.2 mg (106 pmol) of Grubbs second generation. Heat the solution for 10 min at 60 ° C in the microwave. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified over Biotage 25-M silica column (purifier: hept / AcOEt 45/55). Product 33 (130.4 mg, Rf = 0.33 under the purification conditions used) is obtained as a beige solid.

(ES-) = 315 [(M + HCOOH) -H] \ 269 [MH] "1H NMR (300 MHz, DMSO-d6): δ (ppm) = 5.8 (dd, 1H, J = 6 Hz and 16 Hz ), 5.48 (dd, 1H, J = 4.5 Hz and 16 Hz), 5.16 (br s, 2H), 4.29 (m, 2H), 4.25 (d, 1H, J = 4.5 Hz), 3.95 (dd, 1H, J = 3 Hz and 9 Hz), 3.42 (s, 3H), 1.96 (m, 1H), 1.66 (m, 4H), 1.15 (m, 6H)

Step 2: Preparation (2R, 3R, 4S, 5R, 6E) -7-cyclohexyl -3,4,5-trihydroxy-2-methoxy -N [(3R) -5-methyl-4-oxo 2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]

In a 20 mL single neck, introduce 120 mg (444 pmol) of 15 33, 130.4 mg (533 pmol) of 11.177 mg (1.065 mmol) of sodium 2-ethylhexanoate in 6 mL of THF. The solution is allowed to stir at room temperature for 1 week. The solution is then taken up with 6 ml CH 2 Cl 2, then washed with 2 x 5 ml 0.5 N HCl, then 5 ml water. The aqueous phase is then extracted with 2.5 ml of CH2 Cl2, then the organic phases are combined, dried over sodium sulfate, then filtered. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified over a Biotage 12-S silica column (purifier: hept / AcOEt 15/85). The Ex11 product (91.1 mg, Rf = 0.24 under the purification conditions used) is obtained as a white solid.

MS: m / z (ES +) = 979 [2M + Na] +, 501 [M + Na] +, 479 [M + H] +, 461 [(M-H2 O) + H] + 1H NMR (400 MHz, DMSO-d 6): δ (ppm) = 8.28 (d, 1H, J = 8Hz), 7.70 (d, 1H, J = 8Hz), 7.60 (m, 2H), 7.37 (m, 1H), 5.57 (dd , 1H, J = 6.5 Hz and 15 Hz), 5.35 (dd, 1H, J = 6.5 Hz and 15 Hz), 4.58 (br s, 1H), 4.44 (m, 1H), 4.35 (br s, 2H); 3.93 (t, 1 Η, J = 6.5 Ηζ), 3.69 (d, 1 Η, J = 8 Ηζ), 3.50 (m, 1 Η), 3.44 (m, 1Η), 3.40 (m, 1H), 3.36 ( s, 3H), 3.23 (s, 3H), 3.10 (t, 1H, J = 12Hz), 1.92 (m, 1H), 1.65 (m, 4H), 1.15 (m, 6H)

Ex12: (2R.3R, 4S, 5R, 6E) -7- (2-fluoro-phenyl -3,4,5-trihydroxy-2-methoxy-N [(3R) -5-methyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enamide

<formula> formula see original document page 39 </formula>

Step 1: Preparation of (3R, 4R, 5S) -5 - [(1R, 2E) -3- (2-fluoro phenyl) -1-hydroxy prop-2-en-1-yl] -4-hydroxy-3 -methoxy dihydrofuran-2- (3H) -one (34)

<formula> formula see original document page 39 </formula>

In a 5 mL vial, introduce 100 mg (0.53 mmol) of 29, 4 mL of CH 2 Cl 2, 633 μL (5.3 mmol) of 2-fluoro styrene, then 90.2 mg (106 μmol) of Grubbs second generation. Heat the solution for 10 min at 60 ° C in the microwave. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified over 25-M biotage silica column (scrubber: hept / AcOEt 40- / 60). Product 34 (64.4 mg, R = 0.24 under the purification conditions used) is obtained as a white solid.

(ES ") = 327 [(M + HCOOH) -H]" f 281 [M-H] -

1H-NMR (300 MHz, DMSO-d6): δ (ppm) = 7.61 (t, 1H, J = 9 Hz), 7.31 (m, 1H), 7.19 (t, 2H, J = 9 Hz), 6.89 (d , 1H, J = 16.1 Hz), 6.50 (dd, 1H, J = 4.9 Hze 16.1 Hz), 5.55 (d, 2H, J = 5.5 Hz), 4.49 (m, 1H), 4.42 (m, 1H), 4.28 (d, 1H, J = 4.3 Hz), 4.09 (dd, 1H, J = 2.8 Hz and 8.3 Hz), 3.43 (s, 3H)

Step 2: Preparation of (2R, 3R, 4S, 5R, 6E) -7- (2-fluoro phenyl) -3,4,5-trihydroxy-2-methoxy -N [(3R) -5-methyl-2 4-oxo -2,3,4,5-tetrahydro-1,5-benzo thiazepin-3-yl] hept-6-enamide (Ex12) <formula> formula see original document page 40 </formula>

In a 30 mL single-neck, introduce 60 mg (212 pmol) of 34, 62.4 mg (2555 pmol) of 11.53 mg (319 pmol) of sodium 2-ethylhexanoate in 2.5 mL of THF. The solution is allowed to stir at room temperature for 6 days. The solution is then taken up in 5 mL CH 2 Cl 2, then washed with 4 mL 0.5 N HCl, then 4 mL water. The aqueous phase is then extracted with 2 x 5 μmol of CH 2 Cl 2, then the organic phases are combined, dried over sodium sulfate, then filtered. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified on a Biotage 12-M silica column (purifier: CH 2 Cl 2 / Iso-propanol 98/2). Ex12 (45.7 mg, Rf = 0.37 under the purification conditions used) is obtained as a white solid.

MS: m / z (ES +) = 491 [M + H] +, 473 [(M-H2 O) + H] + (ES-) = 535 [(M + HCOOH) -H] \ 489 [M-H] "

1H-NMR (400 MHz, DMSOd6): δ (ppm) = 8.27 (d, 1H, J = 8Hz), 7.65 (d, 1H, J = 8Hz), 7.54 (m, 3H), 7.32 (m, 1H) , 7.26 (m, 1H), 7.16 (m, 2H), 6.65 (d, 1H, J = 16 H), 6.38 (dd, 1H, J = 6 Hz and 16 Hz), 4.95 (d, 1H, J = 4 Hz), 4.55 (d, 1H, J = 6 Hz), 4.47 (d, 1H, J = 6.5 Hz), 4.41 (m, 1H), 4.18 (m, 1H), 3.70 (d, 1H, J = 8 Hz), 3.53 (m, 1H), 3.44 (m, 1H), 3.42 (m, 1H), 3.28 (s, 3H), 3.20 (s, 3H), 3.07 (t, 1H, J = 12 Hz)

Ex13: (2R.3R, 4S, 5R, 6E) -7- (4-fuoro phenyl) -3,4,5-trihydroxy-2-methoxy-N [(3R) -5-methyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enamide

<formula> formula see original document page 40 </formula>

Step 1: Preparation of (3R, 4R, 5S) -5 - [(1R, 2E) -3- (4-fluoro phenyl) -1-hydroxy prop-2-en-1-yl] -4-hydroxy-3 - methoxy dihydrofuran-2 (3H) -one (35) In a 5mL flask, enter 100 mg (0.53 mmol) of 29.4 ml of CH2Cl2, 636 μΙ_ (5.3 mmol) of 4-fluoro styrene, then 90.2 mg (106 μmol) second generation Grubbs catalyst. Heat the solution for 10 minutes at 60 ° C in the microwave. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified over 25-M Biotage silica column (scrubber: 9/1 CH 2 Cl 2 / Isopropanol). Product 35 (99.2 mg, Rf = 0.15 under the purification conditions used) is obtained as a white solid.

1H-NMR (300 MHz, DMSO-d6): δ (ppm) = 7.5 (dd, 2H, J = 6 Hz and 9 Hz), 7.17 (t, 2H, J = 9 Hz), 6.76 (d, 1H, J = 16 Hz), 6.33 (dd, 1H, J = 6 Hz and 15 Hz), 5.52 (br s, 1H), 5.46 (d, 1H, J = 5.5 Hz), 4.46 (m, 1H), 4.42 ( m, 1H), 4.28 (d, 1H, J = 4.5 Hz), 4.08 (dd, 1H, J = 3 Hz and 9 Hz), 3.42 (s, 3H)

Step 2: Preparation (2R, 3R, 4S, 5R, 6E) -7- (4-fluoro phenyl) -3,4,5-trihydroxy-2-methoxy -N [(3R) -5-methyl-4 -oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enamide (Ex13)

<formula> formula see original document page 41 </formula>

In a 30 ml single neck, introduce 90 mg (319 pmol) of 35, 93.6 mg (383 Mmol) of 11,127.2 mg (765 μηαοΙ) of sodium 2-ethylhexanoate in 4 mL of THF. The solution is allowed to stir at room temperature for 28 hours. The solution is then taken up in 6 mL CH 2 Cl 2, then washed with 5 mL 0.5 N HCl, then 5 mL water. The aqueous phase is then extracted with 2.5 mL of CH 2 Cl 2, then the organic phases are combined, dried over sodium sulfate, then filtered. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified on a Biotage 12-M silica column (scrubber: Hept / A-COOt 15/85). Ex13 (55.5 mg, Rf = 0.17 under the purification conditions used) is obtained as a white solid.

MS: m / z (ES +) = 513 [M + Na] +, 491 [M + H] +

(ES-) = 535 [(M + HCOOH) -H] ", 489 [M-H] -

1H-NMR (300 MHz, DMSO-d6): δ (ppm) = 8.26 (d, 1H, J = 8Hz), 7.65 (d, 1H, J = 8Hz), 7.56 (m, 2H), 7.43 (dd, 2H, J = 6Hz and 9Hz), 7.32 (m, 1H), 7.13 (t, 2H, J = 9Hz), 6.52 (d, 1H, J = 16Hz), 6.20 (dd, 1H, J = 6 Hz and 16 Hz), 4.86 (d, 1H, J = 4 Hz), 4.49 (d, 1H, J = 6 Hz), 4.44 (d, 1H, J = 6.5 Hz), 4.40 (m, 1H), 4.15 (m, 1H), 3.70 (d, 1H, J = 8 Hz), 3.53 (m, 1H), 3.47 (m, 1H), 3.45 (m, 1H), 3.28 (s, 3H), 3.19 (s , 3H), 3.07 (t, 1H, J = 12 Hz)

Ex14: (2R.3R, 4S, 5R, 6E) -3,4,5-trihydroxy-5 - [(1R, 2E) -1-hydroxy-3-phenyl prop-2-en-1-yl] -3-methoxy dihydrofuran-2- (3H) -one) (36)

<formula> formula see original document page 42 </formula>

In a 5 mL vial, introduce 100 mg (0.53 mmol) 29, 4 mL CH 2 Cl 2, 615 pL (5.3 mmol) styrene, then 90.2 mg (106 pmol) second generation Grubbs catalyst . Heat the solution for 10 minutes at 60 ° C in the microwave. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified over Biotage 25-M silica column (purifier: CH 2 Cl 2 / Iso-propanol 98/2). Product 36 (79.6 mg, Rf = 0.24 under the purification conditions used) is obtained as a brown solid.

MS: m / z (ES ") = 527 [2M-H]", 309 [(M + HCOOH) -H] ", 263 [M-H] -

1H-NMR (300 MHz, DMSOd6): δ (ppm) = 7.45 (d, 2H, J = 7.5 Hz), 7.35 (t, 2H, J = 7.5 Hz), 7.25 (t, 1H, J = 7.5 Hz), 6.77 (d, 1H, J = 16 Hz), 5.88 (dd, 1H, J = 5.5 Hz and 16 Hz), 5.54 (d, 1H, J = 3 Hz), 5.46 (d, 1H, J = 5 Hz) , 4.48 (m, 1H), 4.42 (m, 1H), 4.48 (d, 1H, J = 4 Hz), 4.09 (dd, 1H, J = 3 Hz and 9 Hz), 3.41 (s, 3H)

Step 2: Preparation of (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy -N [(3R) -5-methyl-4-oxo -2,3,4 , 5-tetrahydro-1,5-benzothiazepin-3-yl] -7-phenylhept-6-enamide (Ex14)

<formula> formula see original document page 42 </formula> In a 20 mL single neck, enter 70 mg (265 μιτιοΙ) of 36, 77.8 mg (318 pmol) of 11, 106 mg (636 μιηοΙ) of 2- sodium ethyl hexanoate in 4 mL of THF. The solution is allowed to stir at room temperature for 43 hours. The solution is then taken up with 6 ml CH 2 Cl 2, then washed with 2 x 5 ml 0.5 N HCl, then 5 ml water. The aqueous phase is then extracted with 2.5 ml of CH2 Cl2, then the organic phases are combined, dried over sodium sulfate, then filtered. The solvent is then evaporated to dryness under reduced pressure, then the residue is purified over a Biotage 12-S silica column (purifier: hept / AcOEt 15/85). Ex14 (62.4 mg, Rf = 0.3 under the purification conditions used) is obtained as a white solid.

MS: m / z (ES +) = 495 [M + Na] +, 473 [M + H] +

(ES +) = 517 [(M + HCOOH) -H] ·, 471 [MH] "1H NMR (300 MHz, DMSO-d6): δ (ppm) = 8.26 (d, 1H, J = 8 Hz), 7.65 (d, 1H, J = 8Hz), 7.55 (m, 2H), 7.39 (d, 2H, J = 6.5Hz), 7.33 (m, 2H), 7.29 (m, 1H), 7.21 (t, 1H), 6.53 (d, 1H, J = 16Hz), 6.25 (dd, 1H, J = 6Hz and 16Hz), 5.34 (d, 1H, J = 4.5Hz), 4.48 (d, 1H, J = 6Hz) , -4.44 (d, 1H, J = 6.5 Hz), 4.38 (m, 1H), 4.15 (m, 1H), 3.70 (d, 1H, J = 7.5 Hz), 3.53 (m, 1H), 3.46 (m 3.42 (m, 1H), 3.32 (s, 3H), 3.20 (s, 3H), 3.06 (t, 1H, J = 12 Hz) Ex15: (2R, 3R, 4S, 5R, 6E) - 3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -N [(3R) -

Step 1: Preparation of 2-fluoro -3-nitro biphenyl (37) <formula> formula see original document page 44 </formula>

In a 50 mL flask under stirring and argon atmosphere containing 10 mL of water, 3 mL of dioxane and 500 mg of 17 (2.273 mmol), 277 mg of phenyl boronic acid (2.273 mmol), 46, 41 mg of 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (C35H30Cl4FeP2Pd, MW 816.65, 0.057 mmol) and 2.96 g Cesium carbonate (9.09 mmol). The medium is heated at 100 ° C for 3 hours. Then 20 ml of AcOEt are added and washed with 2 times 20 ml of water. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The crude is chromatographed over a silica cartridge (30 g), purified with heptane / AcOEt (gradient AcOEt: 10 to 50%). 360 mg of expected product 37 (yellow oil) is collected.

El: 217+ '

1H-NMR (400 MHz, DMSO-d6), δ (ppm): From 7.45 to 7.63 (m, 6H); 7.91 (dt, J = 2.0 and 9.0 Hz, 1H); 8.14 (dt, J = 2.0 and 9.0 Hz, 1H).

Step 2: Preparation of N - [(2,2-dimethyl propanoyl) oxy] -S- (3-nitro biphenyl-2-yl) -L-cysteine (38)

<formula> formula see original document page 44 </formula>

In a 25 mL triple neck containing 367 mg and L-Boe-Cys-OH (1.657 mmol), 2.5 mL water and 402 mg NaHCO3 (4.769 mmol), a solution is added dropwise. of 37 (360 mg, 1.657 mmol) in 2.8 mL of ethanol. The medium is refluxed for 6 hours, then ethanol is evaporated and 5 mL of distilled water is added. The aqueous phase is then washed twice with ether (5 mL), once the ether phase is decanted, the aqueous phase is brought to pH2-3 with HCl (1N), and extracted twice with 5 mL. from AcOEt. The organic phases are combined, dried over MgSO4, filtered and finally evaporated to dryness. 0.81 g of crude product 38 is obtained which is used directly for the next stage. 1H-NMR (400 MHz1 DMSO-d6), δ (ppm): 1.32 (s, 9H); from 2.39 to 2.57 (partially hidden, 2H); 3.57 (m, 1H); 6.77 (d, J = 8.0 Hz, 1H); from 7.40 to 7.55 (m, 5H); 7.59 (broad d, J = 8.0 Hz 1H); 7.65 (t, J = 8.0 Hz, 1H); 7.86 (d lar, J = 8.0 Hz, 1H); 12.15 (m broad, 1H).

Step 3: Preparation of S- (3-Amino Biphenyl-2-yl) -N - [(2,2-Dimethyl Propanoyl) Oxy] -L-Cysteine (39)

In an autoclave containing 810 mg of 38 (1.936 mmol), 69.84 mg Pd / C (10%) and 20 mL MeOH was hydrogenated under 5 barium for 10 hours at 20 ° C. After filtration of the catalyst over celite, the solvent is evaporated and 580 mg of expected product 39 is obtained which is used directly for the next step.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.33 (s, 9H); from 2.60 to 2.75 (m, 2H); 3.81 (m, 1H); 5.60 (m high, 2H); 6.47 (d, J = 8.0 Hz 1H); 6.78 (d, J = 8.0 Hz, 1H); 6.89 (d, J = 8.0 Hz, 1H); 7.09 (t, J = 8.0 Hz, 1H); from 7.24 to 7.41 (m, 5H); 12.2 (m high, 1H).

Step 4: Preparation of (3R) -3 - {[(2,2-dimethyl propanoyl) oxy] amino} -9-phenyl -2,3-dihydro-1,5-benzothiazepin-4 (5H) - one (40)

In a 25 mL triple neck, containing 580 mg of 39 (1.493 mmol), 7 mL of DMF, 0.269 mL of diethyl cyanophosphonate (289.4 mg, 1.744 mmol) is introduced at 0 ° C, and 10 minutes then 0.201 ml TEA (1.43 mmol). The reaction medium is stirred at 0 ° C for 2 hours. 20 ml of EtOAc are added, then washed twice with 20 ml of distilled water. The organic phase is dried over filtered MgSO4, then evaporated to dryness. The crude (600 mg of yellow oil) is chromatographed on a silica cartridge (30 g) and with a heptane / AcOEt scrubber (gradient AcOEt: 10 to 50%). 410 mg of expected product 40 (white solid) is obtained.

1H-NMR (400 MHz, DMSO-d6), δ (ρρηι): 1.35 (s, 9H); 3.02 (t, J = 12.0 Hz, 1H); 3.45 (dd, J = 7.5 and 12.0 Hz, 1H); 4.20 (m, 1H); from 7.12 to 7.25 (m, 3H); from 7.33 to 7.51 (m, 6H); 10.05 (s, 1H).

Step 4: Preparation of (3R) -3-Amino -9-phenyl -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride (41)

<formula> formula see original document page 46 </formula>

In a 50 mL flask containing 410 mg of 40 (1.107 mmol), 8 mL of a solution of hydrochloric acid in dioxane (4M) is added. Stir for 4 hours at RT under argon. A white precipitate forms which is dried, washed with 3 mL dioxane, then 5 mL isopropyl ether. Thus 260 mg of amine 41 (white solid) is obtained as hydrochloride.

1H-NMR (300 MHz, DMSO-d6) δ (ppm): 3.17 (t, J = 12.0 Hz 1H); 3.65 (dd, J = 8.0 and 12.0 Hz, 1H); 4.08 (dd, J = 8.0 and 12.0 Hz, 1H); 7.21 (dd, J = 1.5 and 8.0 Hz, 1H); 7.28 (dd, J = 1.5 and 8.0 Hz, 1H); from 7.35 to 7.49 (m, 5H); 7.52 (t, J = 8.0 Hz, 1H); 8.39 (bs, 3H); 10.65 (s, 1H).

Step 5: Preparation of (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -N [(3R) -4-oxo -9-phenyl -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] non-6-enamide (Ex15)

<formula> formula see original document page 46 </formula> 100 mg of 5 (409 μmol), 151 mg of 41 (491 pmol), 102 are placed successively in a 25 mL flask under agitation and under argon atmosphere. sodium 2-ethylhexanoate (0.61 mmol) in 2.3 mL of THF. Stirring is continued at RT for 24 hours. Concentrate the reaction medium to dryness. The residues are chromatographed on a silica cartridge (15 g, gradient CH 2 Cl 2 / MeOH: 10% MeOH purifier). 145 mg of expected product Ex15 is collected.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 0.96 (s, 9H); 3.10 (t, J = 12.0 Hz, 1H); 3.22 (s, 3H); 3.30 (hidden, 1H); from 3.40 to 3.55 (m, 2H); 3.69 (d, J = 8.0 Hz, 1H); 3.94 (m, 1H); 4.29 (m, 2H); 4.54 (m, 2H); 5.30 (dd, J = 7.0 and 16.0 Hz, 1H); 5.63 (d, J = 16.0 Hz, 1H); 7.19 (broad d, J = 7.5 Hz, 1H); 7.23 (broad d, J = 7.5 Hz, 1H); from 7.35 to 7.46 (m, 5H); 7.49 (t, J = 7.5 Hz, 1H); 8.25 (d, J = 8.0 Hz, 1H); 10.2 (s, 1H).

Ex 16: (2R, 3R, 4S, 5R, 6E) -N - [(3R) -9- (3-cyano phenyl) -4-oxo -2,3,4,5-tetrahydro-1,5-one benzo thiazepin-3-yl] -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl non-6-enamide

<formula> formula see original document page 47 </formula>

Step 1: Preparation of 2'-fluoro -2'-nitro biphenyl -3-carbonitrile (42)

<formula> formula see original document page 47 </formula>

In a 50 mL flask under stirring and argon atmosphere containing 10 mL of water, 3 mL of dioxane and 500 mg of 17 (2.273 mmol), 334 mg of 3-cyano-phenyl boronic acid (2.273 mmol) are introduced. ), 46.41 mg of 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (C35H30Cl4FeP2Pd, MW 816.65, 0.057 mmol) and 2.96 g cesium carbonate (9.09 mmol). The medium is heated at 100 ° C for 3 hours. Then 20 ml of AcOEt are added and washed with 2 times 20 rhL of water. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The crude is chromatographed over a silica cartridge (30 g), purified with heptane / AcOEt (gradient AcOEt: 10 to 50%). 230 mg of expected product 42 (white solid) is collected. 1H-NMR (500 MHz, DMSO-d6), δ (ppm): 7.59 (t, J = 8.0 Hz, 1H); 7.77 (t, J = 8.0 Hz, 1H); from 7.93 to 8.04 (m, 3H); 8.12 (bs, 1H); 8.22 (dt, J = 2.0 and 8.0 Hz, 1H).

Step 2: Preparation and S- (3'-cyano -3-nitro biphenyl-2-yl) -N - [(2,2-dimethyl propanoyl) oxy] -L-cysteine (43)

<formula> formula see original document page 48 </formula>

In a 25 mL triple neck containing 210 mg and L-Boc-Cys-OH (0.950 mmol), 2.5 mL water and 231 mg NaHCO3 (2.746 mmol), a solution of 42 (360 mg, 1.657 mmol) in 3.0 mL ethanol. The medium is refluxed for 2 hours, then ethanol is evaporated and 5 mL of distilled water is added. The aqueous phase is then washed twice with ether (10 mL), once the ether phase is decanted, the aqueous phase is brought to pH2-3 with HCl (1N), and extracted twice with 10 mL of EtOAc. . The phosphates are combined, dried over MgSO4, filtered and finally evaporated to dryness. 0.41 g of crude product 43 is obtained which is used directly for the next stage. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.33 (s, 9H); from 2.47 to 2.60 (partially hidden, 2H); 3.54 (m, 1H); 6.79 (d, J = 8.0 Hz, 1H); from 7.63 to 7.73 (m, 3H); from 7.84 to 7.95 (m, 3H); 7.98 (bs, 1H); 12.55 (broad m, 1H). Step 3: Preparation of S- (3-Amino-3'-cyano biphenyl-2-yl) -N - [(2,2-dimethyl propanoyl) oxide] -L-cysteine (44)

<formula> formula see original document page 48 </formula> In an autoclave containing 410 mg of 43 (0.925 mmol), 41 mg Pd / C (10%) and 20 ml MeOH1 is hydrogenated under 7 barias for 10 minutes. hours at 20 ° C. After filtering the catalyst over celite. The solvent is evaporated and 350 mg of expected product 44 is obtained which is used directly for the next step.

1H-NMR (400 MHz, DMSOd6), δ (ppm): 1.32 (s, 9H); from 2.60 to 2.79 (m, 2H); 3.72 (m, 1H); 5.70 (m high, 2H); 6.48 (broad d, J = 8.0 Hz, 1H); 6.70 (broad d, J = 8.0 Hz, 1H); 6.80 (broad d, J = 8.0 Hz, 1H); 7.11 (t, J = 8.0 Hz, 1H); from 7.52 to 7.83 (m, 4H); 12.5 (m high, 1H).

Step 4: Preparation of 3 - [(3R) -3 - {[(2,2-dimethyl propanoyl) oxy] amino} -4-oxo-2,3,4,5-tetrahydro-1,5-benzo thiazepin-9-yl] benzonitrile (45)

<formula> formula see original document page 49 </formula>

In a 25 mL triple neck containing 350 mg of 41 (0.866 mmol), 4.1 mL of DMF, 0.153 mL of diethyl cyan phosphonate (0.164 mg, 1.01 mmol), and 10 mL are introduced at 0 ° C. minutes later, 0.114 ml TEA (0.811 mmol). The reaction medium is stirred at 0 ° C for 2 hours. 20 ml of EtOAc are added, then washed twice with 20 ml of distilled water. The organic phase is dried over MgSO 4, filtered, then evaporated to dryness. The crude is chromatographed over a silica cartridge (15 g) with a CH 2 Cl 2 / MeOH scrubber (gradient MeOH: 0 to 3%). 139 mg of expected product 45 (orange yellow solid) is obtained.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.34 (s, 9H); 3.02 (t, J = 12.0 Hz, 1H); 3.54 (dd, J = 7.5 and 12.0 Hz, 1H); 4.21 (m, 1H); from 7.19 to 7.30 (m, 3H); 7.50 (t, J = 8.0 Hz, 1H); 7.63 (t, J = 8.0 Hz, 1H); 7.79 (broad d, J = 8.0 Hz, 1H); 7.83 (broad d, J = 8.0 Hz, 1H); 7.98 (bs, 1H); 10.05 (s, 1H).

Step 4: Preparation of 3 - [(3R) -3-Amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-9-yl] benzonitrile hydrochloride (46) <formula > formula see original document page 50 </formula>

In a 25 mL flask containing 139 mg of 45 (0.352 mmol), 2.6 mL of a solution of hydrochloric acid in dioxane (4M) is added. Stir for 4 hours at RT under argon. A white precipitate forms which is dried, washed with 3 mL dioxane, then 5 mL isopropyl ether. Thus 72 mg of amine 46 (white solid) as hydrochloride are obtained.

1H-NMR (300 MHz, DMSO-d6), δ (ppm): 3.19 (t, J = 12.0 Hz, 1H); 3.68 (dd, J = 7.5 and 12.0 Hz, 1H); 4.15 (dd, J = 7.5 and 12.0 Hz, 1H); 7.25 (broad d, J = 8.0 Hz, 1H); 7.32 (broad d, J = 8.0 Hz, 1H); 7.57 (t, J = 8.0 Hz, 1H); 7.69 (t, J = 8.0 Hz, 1H); 7.77 (broad d, J = 8.0 Hz, 1H); 7.89 (broad d, J = 8.0 Hz, 1H); 7.92 (bs, 1H); 8.31 (bs, 3H); 10.7 (s, 1H).

Step 5: Preparation (2R, 3R, 4S, 5R, 6E) -N - [(3R) -9- (3-cyano phenyl) -4-oxo-2,3,4,5-tetrahydro-1, 5-benzothiazepin-3-yl] -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl non-6-enamide (Ex16)

<formula> formula see original document page 50 </formula>

In a Wheatton tube successively, 55 mg of 5 (225 pmol), 74.7 mg of 46 (225 μmol), 74 mg of sodium 2-ethylhexanoate (under agitation and under argon atmosphere) 0.44 mmol) in 1.3 mL of THF. Stirring is continued at RT for 48 hours. Concentrate the reaction medium to dryness. The residues are chromatographed on a silica cartridge (5 g, gradient CH 2 Cl 2 / MeOH: 10% MeOH purifier). 200 mg of expected product are collected Ex16 (white solid) 1 H NMR (400 MHz, DMSO-d 6), δ (ppm): 0.96 (s, 9H); 3.12 (t, J = 12.0 Hz, 1H); 3.22 (s, 3H); 3.30 (hidden, 1H); from 3.53 to 3.57 (m, 2H); 3.69 (d, J = 8.0 Hz, 1 Η); 3.94 (m, 1Η); 4.24 (d, J = 7.0 Hz, 1Η); 4.29 (broad d, J = 6.5 Hz, 1 Η); 4.53 (m, 2H); 5.30 (dd, J = 7.0 and 16.0 Hz, 1H); 5.63 (d, J = 16.0 Hz, 1H); 7.23 (broad d, J = 7.5 Hz 1H); 7.30 (broad d, J = 7.5 Hz, 1H); 7.52 (t, J = 7.5 Hz, 1H); 7.65 (t, J = 7.5 Hz, 1H); 7.75 (broad d, J = 7.5 Hz, 1H); 7.85 (broad d, J = 7.5 Hz 1H); 7.91 (bs, 1H); 8.29 (d, J = 8.0 Hz, 1H); 10.2 (s, 1H).

Ex17: (2R, 3R, 4S, 5R, 6E) -N - [(3R) -6-fluoro-4-oxo-2,3,4,5-tetrahydro-1,5-benzo thiazepin-3-one yl] -3,4,5-trihydroxy-2-m2toxy-8,8-dimethyl non-6-enamide

<formula> formula see original document page 51 </formula>

Step 1: Preparation N - [(2,2-Dimethylpropanoyl) oxide] -S- (3-fluoro-2-nitropenyl) -L-cysteine (48)

<formula> formula see original document page 51 </formula>

In a 50 mL triple neck containing 2.78 g L-Boc-Cys-OH (12.57 mmol), 22 mL water and 3.05 g NaHCO3 (36.33 mmol) a solution of 2,6-difluoro-nitrobenzene 47 (2.0 g, 12.57 mmol) in 26 mL of ethanol. The reaction medium is left at RT for 1 night, then the medium is washed at 75 ° C for 1 hour. Ethanol is evaporated, the aqueous phase is then washed with ether (20 ml), once the ether phase is decanted, the aqueous phase is brought to pH2-3 with HCl (1N), and 2 times with 25 mL EtOAc. The organic phases are combined, dried over MgSO4, filtered and finally evaporated to dryness. 0.129 g of crude product 48 (yellow oil) is obtained which is used directly by the next stage.

1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.36 (s, 9H); 3.24 (dd, J = 10.0 and 13.5 Hz, 1H); 3.53 (dd, J = 5.0 and 13.5 Hz, 1H); 4.08 (m, 1H); 7.20 (d, J = 8.0 Hz 1H); 7.44 (t, J = 8.0 Hz, 1H); 7.57 (t, J = 8.0 Hz, 1H); 7.69 (dt, J = 6.0 and 8.0 Hz, 1H); 12.8 (m broad, 1H).

Step 2: Preparation of S- (2-Amio-3-fluoro phenyl) -N - [(2,2-dimethyl propanoyl) oxy] L-cysteine (49)

In an autoclave containing 790 mg of 48 (2.192 mmol), 79 mg of Pd / C (10%) and 20 mL of ethanol, hydrogenate under 7 bariums for 10 hours at 20 ° C. After filtration of the catalyst over celite, the solvent is evaporated and 670 mg of expected product 49 (yellow oil) is obtained which is used directly for the next step. ES: m / z = 329 (M-H +)

1H-NMR (400 MHz1 DMSO-d6), δ (ppm): 1.38 (s, 9H); 2.94 (dd, J = 10.0 and 13.5 Hz, 1H); 3.09 (dd, J = 5.0 and 13.5 Hz, 1H); 3.94 (m, 1H); 5.30 (bs, 10 2H); 6.52 (dt, J = 6.0 and 8.0 Hz1 1H); from 6.99 to 7.15 (m, 4H).

Step 3: Preparation of (3R) -3 - {[(2,2-dimethyl propanoyl) oxy] amino} -6-fluoro -2,3-dihydro-1,5-benzothiazepin -4 (5H) -one (50).

<formula> formula see original document page 52 </formula>

In a 25 mL triple neck containing 670 mg 49 (2.028 mmol), 10 mL DMF, 0.366 mL diethyl cyan phosphonate (0.394 mg, 2.41 mmol) is introduced at 0 ° C and 10 minutes thereafter 0.273 ml TEA (1.943 mmol). The reaction medium is stirred at 0 ° C for 2 hours. 30 ml of EtOAc are added, then washed with 2 times 30 ml of distilled water. The organic phase is dried over MgSO4, filtered, then evaporated to dryness. The crude is chromatographed on a silica cartridge (70 g) with a heptane / AcOEt purifier (gradient AcOEt: 8 to 50%). 68.4 mg of expected product 50 (white solid) is obtained.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.33 (s, 9H); 3.09 (t, J = 12.0 Hz, 1H); 3.52 (dd, J = 8.0 and 12.0 Hz, 1H); 4.09 (m, 1H); 7.27 (m, 2H); 7.39 (t, J = 9.0 Hz, 1H); 7.44 (d, J = 8.0 Hz, 1H); 9.96 (s, 1H). Step 4: Preparation of (3R) -3-Amino -6-fluoro -2,3-dihydro-1,5-benzothiazepin-4 (5H) -a hydrochloride (51).

<formula> formula see original document page 53 </formula>

In a 25 ml flask containing 68.4 mg of 50 (0.219 mmol) 1.6 ml of a solution of hydrochloric acid in dioxane (4M) is added. Stir for 4 hours at RT under argon. After concentrating the reaction medium to dryness, 51 mg of amine 51 (yellow solid) as hydrochloride are obtained.

1H-NMR (300 MHz, DMSO-d6), δ (ppm): 3.23 (t, J = 12.0 Hz, 1H); 3.75 (dd, J = 7.5 and 12.0 Hz, 1H); 4.03 (dd, J = 7.5 and 12.0 Hz, 1H); 7.32 (dt, J = 6.0 and 8.0 Hz, 1H); 7.43 (t, J = 8.0 Hz, 1H); 7.50 (d, J = 8.0 Hz, 1H); 8.42 (bs, 3H); 10.55 (s, 1H).

Step 5: Preparation of (2R, 3R, 4S, 5R, 6E) -N - [(3R) -6-fluoro-4-oxo-2,3,4,5-tetrahydro-1,5- benzo thiazepin-3-yl] -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl non-6-enamide (Ex17)

<formula> formula see original document page 53 </formula>

Successively introduced into a Wheatton tube, under agitation and under argon atmosphere, 50 mg of 5 (204 pmol), 51 mg of 51 (204 μmol), 69 mg of sodium 2-ethylhexanoate (0.42 mmol) in 1.2 mL of THF. Stirring is continued at RT for 48 hours. Concentrate the reaction medium to dryness. The residues are chromatographed on a silica cartridge (5 g, gradient CH 2 Cl 2 / MeOH: 10% MeOH purifier). 70 mg of expected product are collected Ex16 (white solid) 1 H-NMR (400 MHz, DMSO-d 6), δ (ppm): 0.96 (s, 9H); 3.18 (t, J = 12.0 Hz, 1H); 3.21 (s, 3H); 3.30 (hidden, 1H); from 3.45 to 3.59 (m, 2H); 3.68 (d, J = 8.0 Hz, 1H); 3.92 (m, 1H); 4.29 (d, J = 7.5 Hz, 2H); 4.42 (m, 1H); 4.52 (d, J = 5.0 Hz, 1H); 5.29 (dd, J = 7.5 and 16.0 Hz, 1H); 5.62 (d, J = 16.0 Hz, 1H); 7.29 (m, 1); 7.40 (t, J = 7.5 Hz, 1Η); 7.48 (d, J = 7.5 Hz, 1Η); 8.23 (d, J = 8.0 Hz 1H); 10.1 (s, 1H).

Ex18: (2R, 3R, 4S, 5R, 6E) - 3,4,5-trihydroxy-2-methoxy-N - [(3R) -6-methoxy-4-oxo-2,3,4,5 -tetrahydro-1,5-benzothiazepin-3-yl] -8,8-dimethyl non-6-enamide

<formula> formula see original document page 54 </formula>

Step 1: Preparation of 1-Fluoro-3-methoxy-2-nitro benzene (52)

<formula> formula see original document page 54 </formula>

In a 100 mL triple neck containing 10 l of THF and 0.255 mL of MeOH, 252 mg of 60% sodium hydride suspended in the oil (6.29 mmol) is added. Stir at RT for 1 hour, and introduce a solution of 2,6-difluoro-nitrobenzene 47 (1.0 g, 6.29 mmol) in 10 mL of THF. The reaction medium is left at RT for 16 hours. 10 ml of EtOAc are added, and washed 2 times with 20 ml of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. 0.93 g of product 52 (cream solid) are obtained.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.95 (s, 3H); 7.15 (broad t, J = 8.0 Hz, 1H); 7.21 (broad d, J = 8.0 Hz, 1H); 7.65 (dt, J = 6.0 and 8.0 Hz, 1H).

Step 2: Preparation of N - [(2,2-Dimethylpropanoyl) oxy] -S- (3-Methoxy-2-nitrophenyl) -L-cysteine acid (53)

<formula> formula see original document page 54 </formula>

In a 100 ml triple neck containing 1.422 g L-Boc-Cys-OH (6.428 mmol), 13 ml water and 1.551 g NaHCO3 (18.58 mmol) a solution of 52 ( 1.1 g, 6.428 mmol) in 17 mL of ethanol. The medium is heated at 100 ° C for 6 hours. Ethanol is evaporated, then the aqueous phase is washed with ether (20 mL), once the ether phase is decanted, the aqueous phase is brought to pH2-3 with HCl (1N), and quenched with 25 mL EtOAc. The organic phases are combined, dried over MgSO4, filtered and finally evaporated to dryness. The residues are chromatographed on a silica cartridge (25 g, CH2 Cl2 / MeOH gradient scrubber: 10% MeOH 1), 2.43 g of product 53 (cream solid) are obtained. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.39 (s, 9H); 3.17 (dd, J = 10.0 and 14.0 Hz, 1H); 3.40 (dd, J = 4.0 and 14.0 Hz1 1H); 3.89 (s, 3H); 4.03 (m, 1H); 7.20 (d, J = 8.0 Hz, 1H); 7.23 (m, 2H); 7.54 (t, J = 8.0 Hz, 1H); 12.8 (m, 1H).

Step 3: Preparation of S- (2-Amino-3-methoxy phenyl) -N - [(2,2-dimethyl propanoyl) oxy] -L-cysteine (54)

<formula> formula see original document page 55 </formula>

In an autoclave containing 2.43 g of 53 (6.53 mmol), 285 mg Pd / C (10%) and 174 mL methanol, hydrogenate under 5 bars for 10 hours at 20 ° C. After filtration of the catalyst over celite, the solvent is evaporated and 1.8 g of expected product 54 (brown oil) is obtained which is used directly for the next step.

Step 4: Preparation of (3R) -3 - {[(2,2-dimethyl propanoyl) oxy] amino} -6-methoxy-2,3-dihydro-1,5-benzothiazepin -4 (5H) -one (55)

<formula> formula see original document page 55 </formula>

In a 100 mL triple neck, containing 1.80 g of 54 (5.26 mmol), 25 mL of DMF, 0.948 mL of diethyl cyano phosphonate (1.019 g, 6.245 mmol) and 10 mL are introduced at 0 ° C. minutes later, 0.708 ml TEA (5.04 mmol). The reaction medium is stirred at 0 ° C for 2 hours. 50 ml of EtOAc are added, then washed with 2 times 50 ml of distilled water. The organic phase is dried over MgSO 4, filtered, then evaporated to dryness. The crude is chromatographed over a silica cartridge (150 g) with a heptane / AcOEt purifier (gradient AcOEt; 10 to 50%). 450 mg of expected product 55 (white solid) is obtained.

1H-NMR (400 MHz1 DMSO-d6), δ (ppm): 1.32 (s, 9H); 3.05 (t, J = 12.0 Hz, 1H); 3.48 (dd, J = 7.0 and 12.0 Hz, 1H); 3.82 (s, 3H); 4.04 (m, 1H); from 7.10 to 7.12 (m, 4H); 9.40 (s, 1H).

Step 5: Preparation of (3R) -3-Amino -6-methoxy -2,3-dihydro-1,5-benzothiazepin -4 (5H) -one hydrochloride (56).

<formula> formula see original document page 56 </formula>

In a 100 mL flask containing 450 mg of 55 (1.387 mmol), 10.4 mL of a solution of hydrochloric acid in dioxane (4M) is added. Stir for 3 hours at RT with stirring. A white precipitate forms, is dried, washed with 3 mL dioxane, then 5 mL isopropyl ether. Thus 259 mg of amine 56 (cream solid) as hydrochloride is obtained.

1H-NMR (300 MHz, DMSO-d6) δ (ppm): 3.19 (t, J = 12.0 Hz 1H); 3.71 (m, 1H); 3.82 (s, 3H); 3.83 (m, 1H); from 7.17 to 7.30 (m, 3H); 8.39 (s, 3H); 10.05 (s, 1H).

Step 6: Preparation of (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy -N - [(3R) -6-methoxy-4-oxo -2,3, 4,5 tetrahydro-1,5-benzothiazepin-3-yl] -8,8-dimethyl non-6-enamide (Ex18).

<formula> formula see original document page 56 </formula>

100 mg of 5 (409 pmol), 107 mg of 56 (409 μmol), 170 mg of sodium 2-ethylhexanoate (1.02 mmol) in a Wheatton1 tube are successively introduced under agitation and under argon atmosphere. 2 mL of THF. Stirring is continued at RT for 24 hours. Concentrate the reaction medium to dryness. The residues are chromatographed on a silica cartridge (12 g, AcOEt purifier). 175 mg of expected product Ex18 (white meringue) is collected.

ES: m / z = 467 (M-H +)

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 0.96 (s, 9H); 3.09 (t, J = 12.0 Hz, 1H); 3.20 (s, 3H); 3.30 (hidden, 1H); from 3.45 to 3.55 (m, 2H); 3.68 (d, J = 8.0 Hz, 1H); 3.82 (s, 3H); 3.92 (m, 1H); from 4.30 to 4.45 (m, 3H); 4.55 (bs, 1H); 5.29 (dd, J = 7.0 and 16.0 Hz, 1H); 5.62 (d, J = 16.0 Hz, 1H); from 7.12 to 7.26 (m, 3H); 8.10 (d, J = 8.0 Hz 1H); 9.58 (s, 1H).

Ex19. (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -N - [(3R) -4-oxo-6-phenoxy-2,3 4,5 tetrahydro-1,5-benzothiazepin-3-yl] -non-6-enaminda

<formula> formula see original document page 57 </formula>

Step 1: Preparation of 1-fluoro-2-nitro-3-phenoxy benzene (57).

<formula> formula see original document page 57 </formula>

In a 50 ml triple neck containing 10 ml DMF and 0.592 g phenol, 252 mg of 60% sodium hydride suspended in the oil (6.29 mmol) is added. Stir at RT for 1 hour, and a solution of 2,6-difluoro-nitrobenzene 47 (1.0 g, 6.29 mmol) in 10 mL of DMF is introduced. The reaction medium is left at RT for 24 hours. 50 ml of EtOAc are added, and washed twice with 20 ml of distilled water. The organic phase is dried over MgS 4, filtered and finally evaporated to dryness. The crude is chromatographed on a silica cartridge (120 g) with a heptane / AcOEt scrubber (gradient AcOEt: 0 to 50%). 1.07 g of expected product 57 (yellow oil) is obtained.

1H-NMR (400 MHz, DMSO-d6) δ (ppm): 6.92 (broad d, J = 8.0 Hz, 1H); 7.17 (broad d, J = 7.5 Hz, 2H); 7.29 (t, J = 7.5 Hz, 1H); 7.36 (broad t, J = 8.0 Hz, 1H); 7.48 (t, J = 7.5 Hz, 2H); 7.65 (dt, J = 6.0 and 8.0 Hz, 1H). Step 2: Preparation M - [(2,2-dimethyl propanpoyl) oxy] -S- (2-nitro-3-phenoxy phenyl) -L-cysteine (58)

<formula> formula see original document page 58 </formula>

In a 25 mL triple neck containing 0.693 g and L-Boc-Cys-OH (3.13 mmol), 6.3 mL water and 0.76 g NaHCO3 (9.05 mmol), a solution is introduced. of 57 (0.73 g, 3.13 mmol) in 8 mL of ethanol. The medium is heated at 75 ° C for 6 hours. Ethanol is evaporated, distilled water is added 10 ml, then the phase is washed twice with ether 10 ml, once the ether phase is decanted, the aqueous phase is brought to pH2-3 with HCl. (1N) and extracted 2 times with 10 mL EtOAc. The organic phases are combined, dried over MgSO4, filtered and finally evaporated to dryness. The residues are chromatographed on a silica cartridge (50 g, gradient CH2 Cl2 / MeOH scrubber: 10% MeOH 1), 760 mg of product 58 (yellow oil) are obtained.

1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.38 (s, 9H); 3.22 (dd, J = 9.0 and 14.0 Hz, 1H); 3.50 (dd, J = 5.0 and 14.0 Hz, 1H); 4.08 (m, 1H); 6.96 (d, J = 8.0 Hz, 1H); 7.10 (d, J = 8.0 Hz, 2H); from 7.18 to 7.28 (m, 2H); from 7.39 to 7.49 (m, 3H); 7.56 (t, J = 8.0 Hz, 1H); 12.85 (broad m, 1H).

Step 3: Preparation of S- (2-Amino-3-phenoxy phenol) -N - [(2,2-dimethyl propanyl) oxy] -1-cysteine (59)

<formula> formula see original document page 58 </formula>

In an autoclave containing 0.76 g of 58 (1.75 mmol), 76 mg Pd / c (10%) and 34.5 Ml methanol, hydrogenate under 5 barias for 10 hours at 20 °. Ç. After filtration of the catalyst over celite, the solvent is evaporated and 0.63 g of expected product 59 (brown oil) is obtained which is used directly for the next step.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.39 (s, 9H); 2.96 (m, 1H); 3.11 (m, 1); 3.98 (m, 1); 5.10 (m broad, 2Η); 6.58 (t, J = 8.0 Hz, 1Η); 6.80 (d, J = 8.0 Hz, 1 Η); 6.92 (d, J = 7.5 Hz, 2H); from 7.00 to 7.20 (m, 3H); 7.34 (t, J = 7.5 Hz, 2H); 12.5 (m high, 1H).

Step 4: Preparation of (3R) -3 - {[(2,2-dimethyl propanoyl) oxy] amino} -6-phenoxy -2,3-dihydro-1,5-benzothiazepin -4 (5H) - one (60)

<formula> formula see original document page 59 </formula>

In a 25 mL triple neck, containing 0.63 g of 59 (1.56 mmol), 7.5 mL of DMF, 0.281 mL of diethyl cyano phosphonate (0.302 g, 1.85) is introduced at 0 ° C. mmol), and 10 minutes later, 0.21 ml TEA (1.49 mmol). The reaction medium is stirred at 0 ° C for 2 hours. 15 ml of EtOAc are added, then washed twice with 15 ml of distilled water. The organic phase is dried over MgSO 4, filtered, then evaporated to dryness. The crude is chromatographed over a silica cartridge (120 g) with a Heptane / AcOEt purifier (in AcOEt gradient: 0 to 30%). 188 mg of expected product 60 (white solid) is obtained.

1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.35 (s, 9H); 3.09 (t, J = 12.0 Hz, 1H); 3.52 (dd, J = 7.0 and 12.0 Hz, 1H); 4.21 (m, 1H); from 6.97 to 7.05 (m, 3H); from 7.08 to 7.18 (m, 2H); 7.21 (t, J = 7.5 Hz, 1H); 7.37 (t, J = 7.5 Hz, 2H); 7.42 (d, J = 7.5 Hz, 1H); 9.81 (s, 1H).

Step 5: Preparation of (3R) -3-Amino -6-phenoxy -2,3-dihydro-1,5-benzothiazepin -4- (5H) -one hydrochloride (61)

<formula> formula see original document page 59 </formula>

In a 100 mL flask containing 188 mg of 60 (0.487 mmol), 3.65 mL of a solution of hydrochloric acid in dioxane (4M) is added. The reaction medium is concentrated to dryness and taken up in 10 mL of isopropyl ether. After filtration, 100 mg of amine 61 (white solid) as hydrochloride is obtained. 1H-NMR (400 MHz1 DMSO-d6), δ (ρρm): 3.22 (t, J = 12.0 Hz, 1Η); 3.79 (dd, J = 7.0 and 12.0 Hz, 1 Η); 4.08 (dd, J = 6.0 and 12.0 Hz 11); 6.97 (broad d, J = 7.5 Hz1 1 Η); 7.04 (d, J = 7.5 Hz, 2Η); 7.19 (t, J = 7.5 Hz 1H); 7.23 (t, J = 8.0 Hz, 1 Η); 7.42 (m, 3H); 8.44 (bs, 3H); 10.45 (s, 1H).

Step 6: Preparation of (2R.3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -N - [(3R) -4-oxo-6- phenoxy -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] non-6-enamide (Ex19).

<formula> formula see original document page 60 </formula>

Subsequently, 75 mg of 5 (307 μmol), 99.1 mg of 61 (307 μmol), 127 mg of sodium 2-ethylhexanoate (under stirring and under argon atmosphere) 0.77 mmol) in 1.6 ml of THF. Stirring is continued at RT for 48 hours. Concentrate the reaction medium to dryness. The residues are chromatographed on a silica cartridge (5 g, AcOEt purifier). 56 mg of expected product Ex19 (white meringue) is collected.

1H-NMR (400 MHz1 DMSO-d6), δ (ppm): 0.95 (s, 9H); 3.12 (t, J = 12.0 Hz, 1H); 3.19 (s, 3H); 3.30 (hidden, 1H); 3.50 (m, 1H); 3.54 (dd, J = 6.5 and 12.0 Hz, TH); 3.69 (d, J = 8.0 Hz, 1H); 3.94 (m, 1H); 4.32 (m, 2H); 4.52 (m, 1H); 4.58 (d, J = 4.5 Hz 1H); 5.30 (dd, J = 6.5 and 16.0 Hz, 1H); 5.62 (d, J = 16.0 Hz, 1H); 7.00 (m, 3H); 7.12 (t, J = 7.5 Hz, 1H); 7.22 (t, J = 7.5 Hz 1H); 7.38 (t, J = 7.5 Hz -1 2H); 7.42 (broad d, J = 7.5 Hz, 1H); 8.19 (d, J = 8.0 Hz, 1H); 9.97 (s, 1H).

Ex20: (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl -N - [(3R) -5-methyl-4-oxo-2 3,4,5-tetrahydro-1,5-benzo thiazepin-3-yl] non-6-enamide

50 mg of 62 (205 μιτιοΙ) (prepared according to the operating method described in step 3 of Ex1) is then successively introduced into a 5 ml flask under agitation and under argon atmosphere from (4S, 4aS, 7R, 7aR) -4 - ((Z) -3,3-dimethyl-but-1-enyl) -7-methoxy -2,2-dimethyl-tetrahydro-furo [3,2-d] - 1,3-dioxin-6-one, obtained minority when preparing 4 according to the operating methods described in Org. Process Res. Dev. 2003, 7 (6), 856-865), 61 mg of 11 (246 pmol ), 51 mg of sodium 2-ethylhexanoate (0.31 mmol) in 1 mL of THF. Stirring is continued at RT for 24 hours. 10 mL of CH 2 CF 3 is added to the reaction medium. Wash with 5 mL HCl (1N) solution. The organic phase is dried over anhydrous magnesium sulfate, filtered, then evaporated to dryness. The crude (0.15 g) is chromatographed on a silica cartridge (5 g, Heptane / AcOEt purifier: 10/90). 68 mg of expected product Ex20 is collected.

ES: m / z = 451 (M-H) -.

1H-NMR (300 MHz, DMSO-d6), δ (ppm): 0.95 (s, 9H); 3.12 (t, J = 12.0 Hz, 1H); 3.19 (s, 3H); 3.30 (hidden, 1H); 3.50 (m, 1H); 3.54 (dd, J = 6.5 and 12.0 Hz, 1H); 3.69 (d, J = 8.0 Hz, 1H); 3.94 (m, 1H); 4.32 (m, 2H); 4.52 (m, 1H); 4.58 (d, J = 4.5 Hz, 1H); 5.30 (dd, J = 6.5 and 16.0 Hz, 1H); 5.62 (d, J = 16.0 Hz, 1H); 7.00 (m, 3H); 7.12 (t, J = 7.5 Hz, 1H); 7.22 (t, J = 7.5 Hz, 1H); 7.38 (t, J = 7.5 Hz, 2H); 7.42 (broad d, J = 7.5 Hz, 1H); 8.19 (d, J = 8.0 Hz, 1H); 9.97 (s, 1H).

Biological activity of prepared products:

On the day of filing, the CaC02-TC7 of the product of example 5 was measured to be Papp single point = 23.10'7 cm.sec'1. This compound has better total metabolic stability (11% and rat metabolism) than the product of example 20 (99%) described in patent application W02006 / 056696.

The antiproliferative activity of the products of the examples in Table 1 was determined by measuring inhibition of cell proliferation of HCT116 cells. Cells are inseminated in a cell culture medium at a concentration of 10,000 cells per well in 0.17 mL medium, and 20 pL of test product with different concentrations and 10 pL of Thymidine [methyl-14C] ( 100 pCi / ml - specific activity 47.90 mCi / mmol; NEN Reference Technologies NEC568 batch 3550-001) are added, then the cells are incubated at 37 ° C and 5% CO 2.

Media used for HCT116 cell culture: 2 mM DMEM L-glutamine medium, 200 µl / ml penicillin, 200 mg / ml streptomycin and 10% (V / V) Fetal Calf Serum (Life Technologies).

After 96 hours, 14Otimidine incorporation is computed on a 1450 Microbeta Wallac Trilux liquid scintillation computer. The R results are expressed in cpm (beats per minute) and converted to percent inhibition of growth Gl% by first subtracting the average number of cpm from wells without B cells and then dividing by the number of cpm. from untreated C-cell wells, comprising 20 μL of product dilution medium containing 1% ethanol. (Gl% = (R - Β) χ 100 / C%).

IC50 values are calculated as an aid to equation 205 of soft XLFit (IDBS company, UK) by nonlinear regression analysis using the Marquardt algorithm (Donald W. MARQUARDT, J. Soc.industry.appl, vol 11, n 2, June 1963).

The products in Table 1 have an IC50 on HCT116 cells generally less than 30 μΜ and preferably less than 100 nM. For example, the product of example 3 has an IC50 of 10 nM and the product of example 5 has an IC50 of 14 nM. The product of example 1 has an IC50 of 9 nM, the product of example 2 has an IC50 of 20 nM, the product of example 4 has an IC50 of 19 nM and the product of example 9 has an IC50 of 7 nM.

Table 1

<table> table see original document page 62 </column> </row> <table> <table> table see original document page 63 </column> </row> <table> <table> table see original document page 64 < / column> </row> <table>

Claims (30)

1. Product of the following general formula (I): <formula> formula see original document page 65 </formula> in which: (a) R1 is independently selected from the group consisting of (C1-C12) alkyl, (C2-C12) alkenyl, (C2 -C12) alkynyl, cycloalkyl, hetero cyclyl, aryl, heteroaryl, cyclo (C1-C12) alkyl alkyl, cyclo (C2 -C12) alkyl alkenyl, cyclo (C2 -C12) alkyl, hetero cyclyl ( C 1 -C 12) alkyl, C 2 -C 12 heterocyclyl alkenyl, C 2 -C 12 hetero cyclyl alkynyl, C 2 -C 12 aryl alkyl, C 2 -C 12 aryl alkenyl, C 2 -C 12 aryl alkynyl, C 1 -C 12 heteroaryl alkyl, C 2 -C 12 hetero aryl alkenyl, C 2 -C 12 hetero aryl alkynyl, the aryl group of each R 1 being optionally substituted by one or more halogens; b) R2 is selected from the group consisting of (C1-C6) alkyl, (C1-C6) aryl alkyl, hetero-aryl (C1-C6) alkyl, aryl, hetero aryl, (C1-C6) alkylthio (C1-C6) alkyl, di (C1-C6) lower alkyl (C1-C6) alkyl, aryloxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkyl; c) R3 is selected from the group consisting of H, COO (R5), CONH (R5), CO (R5), O (R5), R5; d) R4 is independently selected from the group consisting of H, F, Cl, Br, N (R5) 2, NO2, CN, COO (R5), CON (R5) 2, NHCO (R5) 1 NHCOO (R5), OCONH (R5), O (R5), R5, or two substituents R4, attached to 2 adjoining phenyl carbons, together form a cycle selected from alkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R4 . e) m is 0,1,2, 3, or 4; f) X is chosen from S, SO or SO2; g) R5 is independently chosen from double non-binder electrons, H, (C1-C12) alkyl, (C2-C12) alkenyl, (C2-C12) alkynyl, (C1-C12) alkyl halogen, (C1-C12) aryl alkyl, hetero (C 1 -C 12) aryl alkyl, hetero aryl (C 1 -C 12) aryl alkyl, aryl, hetero aryl, cycloalkyl, wherein each R 5 is optionally substituted by at least one substituent chosen from OH, halogen , (C1-C4) alkyl, (C1-C4) alkoxy, aryl (C1-C4) alkyl, aryl, hetero aryl (C1-C4) alkyl, hetero aryl, -N (CH3) 2, -NH2, CONH2, < formula> formula see original document page 66 </formula> each of Rz is independently selected from the group consisting of H, COO (R5), CONH (R5), CON (R5) 2, CO (R5), R5, in which each R5 is independently selected from (C1-C4) alkyl, (C1-C4) alkyl halogen, aryl (C1-C4) alkyl, heteroaryl (C1-C4) alkyl, where each R5 is optionally substituted by one substituent. OH, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, aryl (C1-C4) to alkyl, aryl, (C 1 -C 4) aryl hereto alkyl, hetero aryl; provided that when R1 is (E) -CH = CH-C (CH3) 3, R2 is methyl, X and S in is O, then R3 is not a hydrogen atom, a (3,5-difluoro) (phenyl) methyl or a group -CH 2 -CH = CH 2. Product according to claim 1, characterized in that R1 is chosen from -C (R6) = C (R7) (R8), wherein R6, R7 and R8 are independently selected from H, (C1- C6) alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl. Product according to Claim 2, characterized in that R1 is chosen from (E) -CH = CH-CH (CH3) (C2-H5) 1 (E) -CH = CH-CH (CH3) 2 and (E) -CH = CH-C (CH 3) 3. Product according to Claim 2, characterized in that R1 is chosen from (E) -C (CH3) = CH-CH (CH3) (C2-H5), (E) -C (CH3) = CH -CH (CH 3) 2, and (E) -C (CH 3) = CH-C (CH 3) 3. Product according to any one of claims 1 to -4, characterized in that R2 is methyl. Product according to any one of claims 1 to 5, characterized in that X is S. Product according to any one of claims 1 to 5, characterized in that X is SO. Product according to any one of claims 1 to 5, characterized in that X is SO2. Product according to any one of claims 1 to 8, characterized in that R 3 is independently selected from: methyl, a phenyl methyl group or a (3,5-difluorophenyl) methyl group. Product according to any one of claims 1 to 8, characterized in that R3 is H. Product according to any one of claims 1 to 10, characterized in that R 4 is independently selected from: F, Cl, Br, phenyl, cyano phenyl, trifluoro methyl, methoxy, phenoxy or 2 R 4 substituents attached to R 4. 2 adjacent carbons of phenyl together form a pyrazine cycle. Product according to any one of claims 1 to 10, characterized in that m is 0. Product according to any one of Claims 1 to 12, characterized in that it is chosen from: N - [(1R, 3R) -5- (3,5-difluoro-benzyl) -1,4-dioxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] - ((6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy- 2-methoxy -8,8-dimethyl -non-6-enamide; N - [(1S, 3R) -5- (3,5-difluorobenzyl) -1,4-dioxo -2,3,4,5 - tetrahydro-1,5-benzothiazepin-3-yl] - ((6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8- dimethyl -non-6-enamide; N - [(3R) -5-benzyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] - (6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide; N - [(3R) -5-methyl-4-one oxo -2,3,4,5-tetrahydro -1,5-benzothiazepin-3-yl] - (6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy - 2-methoxy -8,8-dimethyl -non-6-erlamide; N - ((3R) -9-chloro-4-oxo-7-trifluoro methyl-2,3,4,5-tetrahydro-1, 5-benzothiazepin-3-yl) - (6E) - (2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide; N - ((3R) -9 - bromo-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) - (6E) - (2R, 3R, 4S, 5R) -3,4,5 trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide; N - ((3R) -8-chloro-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) - (6E) - (2R, 3R, 4S , 5R) -3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide; (6E) - (2R, 3R, 4S, 5R) -8-ethyl -3,4,5-trihydroxy-2-methoxy -N - ((3R) -5-methyl-4-oxo -2,3 4,5-tetrahydro-1,5-benzothiazepin-3-yl] dec-6-enamide Product according to any one of claims 1 to 12, characterized in that it is chosen from: (2R, 3R, 4S, 5R, 6E) -7-cyclo pentyl -3,4,5-trihydroxy -2-methoxy-N [(3R) -5-methyl-4-oxo -2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enamide; (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy -N [(3R) -5-methyl-4-oxo-2,3,4,5-tetra -hydro-1,5-benzothiazepin-3-yl] undec-6-enamide; (2R, 3R, 4S, 5R, 6E) -7-cyclohexyl -3,4,5-trihydroxy-2-methoxy-N [(3R) -5-methyl-4-oxo -2,3,4 , 5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enamide; (2R, 3R, 4S, 5R, 6E) -7- (2-fluoro phenyl) -3,4,5-trihydroxy-2-methoxy -N [(3R) -5-methyl-4-oxo-2 3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enamide; (2R.3R, 4S, 5R, 6E) -7- (4-fluoro phenyl) -3,4,5-trihydroxy-2-methoxy -N [(3R) -5-methyl-4-oxo-2 3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] hept-6-enamide; (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy -N [(3R) -5-methyl-4-oxo-2,3,4,5-tetra -hydro-1,5-benzothiazepin-3-yl] -7-phenylhept-6-enamide; (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N [(3R) -5-methyl-4-oxo -9-phenyl- 2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] non-6-enamide; (2R, 3R, 4S, 5R, 6E) -N [(3R) -9- (3-cyano phenyl) -4-oxo -2,3,4,5-tetrahydro-1,5-benzo thiazepin - 3-yl] -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enamide; (2R, 3R, 4S, 5R, 6E) -N [(3R) -6-fluoro-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl] - 3,4,5-trihydroxy-2-methoxy -8,8-dimethyl -non-6-enamide; (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy -N [(3R) -6-methoxy-4-oxo-2,3,4,5-tetramethyl hydro -1,5-benzothiazepin-3-yl] -8,8-dimethyl non-6-enamide; (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N [(3R) -4-oxo-6-phenoxy-2,3, 4,5-tetrahydro-1,5-benzothiazepin-3-yl] non-6-enamide; (2R, 3R, 4S, 5R, 6Z) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N [(3R) -5-methyl-4-oxo -2,3, 4,5-Tetrahydro-1,5-benzothiazepin-3-yl] non-6-enamide. Product according to any one of the preceding claims, characterized in that it is in the form: a) non-chiral, or b) racemic, or c) enriched with a stereo isomer, or d) enriched with an enantiomer; and because it is eventually salified. Medicament, characterized in that it comprises a product of formula (I) according to any one of claims 1 to 15, or a salt of addition thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate of the product of formula (I). Pharmaceutical composition, characterized in that it comprises a product of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, hydrate or solvate thereof, as well as by at least one pharmaceutically acceptable excipient. Use of a product according to any one of claims 1 to 15 for the manufacture of a medicament useful for preventing or treating a condition. Use according to claim 18, characterized in that the disease state is cancer. Process for preparing a product of formula (I) according to one of Claims 1 to 15 or (Γ), characterized in that a product of formula (II): <formula> formula see original document wherein R1, R2, R3, R4, X and m are as defined above, is hydrolyzed to a product of formula (I) or (I '). Process according to Claim 20 for the preparation of a product of formula (I) according to one of Claims 1 to 15 or (I '), characterized in that a reaction product is reacted. formula (III): <formula> formula see original document page 70 </formula> wherein R3, R4, X and m are as defined above with a product of formula (IV): <formula> formula see original wherein R1, R2 are as defined above to obtain a product of formula (II). Process for preparing a product of formula (I) according to one of claims 1 to 15 or (I ') characterized in that a product of formula (III) is reacted: <formula> see original document page 70 </formula>, where R3, R4, X and m are as defined above, and a product of formula (V): <formula> formula see original document page 71 </formula> R2 are as defined above to give a product of formula (I) or (I '). A process according to claim 22 for a product of formula (I) according to any one of claims 1 to 15 or (Γ) characterized in that a product of formula (IV): <formula> formula see original document page 71 </formula> wherein R1, R2 are as defined above, hydrolyses to obtain a product of formula (V): <formula> formula see in which R1, R2 are as defined above. A process according to claim 22 for a product of formula (Γ), characterized in that it has a product of formula (III): <formula> formula see original document page 71 </formula> reacts with a product of the following formula (V): <formula> formula see original document page 71 </formula> to obtain a product of the following formula (I '): <formula> formula see original document page 71 </formula> A process according to claim 22 for a product of formula (I) according to any one of claims 1 to -15, or (Γ), characterized in that a product of formula (VII) ): <formula> formula see original document page 72 </formula> where R2 is as defined above undergoes hydrolysis to give a product of formula (VI): <formula> formula see original document where R2 is as defined above, which is metathesis to obtain a product of formula (V): <formula> formula see original document page 72 </formula> for which R1 represents -CH = CH-R11 and R'1 represents a (C1-C6) alkyl, cycloalkyl, hetero cyclyl, aryl or hetero aryl group. A process according to claim 25 for a product of formula (I) according to any one of claims 1 to 15, or (Γ), characterized in that a product of formula ( VII): <formula> formula see original document page 72 </formula> wherein R2 is as defined above is obtained by double dehydration of a product of general formula (VIII): <formula> formula see original document page 72 </formula>, where R2 is as defined above. Products of formula (Γ) and (II) as defined in claims 20 to 26, except those for which R1 is (E) -CH = CH-C (CH3) 3, R2 is methyl, X is S, m is O, and R 3 is a hydrogen atom, a (3,5-difluoro-phenyl) methyl group or a group -CH 2 -CH = CH 2 are an object of the present invention. 28. Products of formula (III), characterized in that X is S, R3 is H, methyl, phenyl methyl or (3,5-difluoro phenyl) methyl and R4 is Cl1 Br, phenyl, cyano phenyl, trifluoro methyl , methoxy or phenoxy, or m have a value of 0, except those for which X is S, m is 0, and R3 is a hydrogen atom or a group (3,5-difluoro-phenyl) -methyl and except those for which X is S, R3 is phenyl methyl and R4 is trifluoro methyl or methoxy. 29. Products of formula (IV) and (V), characterized in that R2 is methyl and R1 is - (E) -CH = CH-C5H9 or - (E) -CH = CH-C6H5, in which phenyl is replaced by a fluorine atom. 30. Products of formula (VI), characterized in that R2 is methyl.